Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use

ABSTRACT

The present invention describes novel nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) inhibitors and novel compositions comprising at least one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or optionally, at least one therapeutic agent, such as, steroids, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4  (LTB 4 ) receptor antagonists, leukotriene A 4  (LTA 4 ) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H 2  antagonists, antineoplastic agents, antiplatelet agents, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics,  Helicobacter pylori  inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof. The present invention also provides novel compositions comprising at least one parent COX-2 inhibitor and at least one nitric oxide donor, and, optionally, at least one therapeutic agent. The present invention also provides kits and methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity; and for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/171,623 filed Dec. 23, 1999 and U.S. Provisional Application No.60/226,085 filed Aug. 18, 2000.

FIELD OF THE INVENTION

The present invention describes novel nitrosated and/or nitrosylatedcyclooxygenase 2 (COX-2) inhibitors and novel compositions comprising atleast one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2)inhibitor, and, optionally, at least one compound that donates,transfers or releases nitric oxide, stimulates endogenous synthesis ofnitric oxide, elevates endogenous levels of endothelium-derived relaxingfactor or is a substrate for nitric oxide synthase, and/or at least onetherapeutic agent. The present invention also provides novelcompositions comprising at least one COX-2 inhibitor. The presentinvention also provides methods for treating inflammation, pain andfever; for treating and/or improving the gastrointestinal properties ofCOX-2 inhibitors; for facilitating wound healing; for treating and/orpreventing renal toxicity; and for treating and/or preventing otherdisorders resulting from elevated levels of cyclooxygenase-2.

BACKGROUND OF THE INVENTION

Nonsteroidal anti-inflammatory compounds (NSAIDs) are widely used forthe treatment of pain, inflammation, and acute and chronic inflammatorydisorders such as osteoarthritis and rheumatoid arthritis. Thesecompounds inhibit the activity of the enzyme cyclooxygenase (COX), alsoknown as prostaglandin G/H synthase, which is the enzyme that convertsarachidonic acid into prostanoids. The NSAIDs also inhibit theproduction of other prostaglandins, especially prostaglandin G₂,prostaglandin H₂ and prostaglandin E₂, thereby reducing theprostaglandin-induced pain and swelling associated with the inflammationprocess. The chronic use of NSAIDs has been associated with adverseeffects, such as gastrointestinal ulceration and renal toxicity. Theundesirable side effects are also due to the inhibition of prostaglandinin the affected organ.

Recently two isoforms of cyclooxygenase, encoded by two distinct genes(Kujubu et al, J. Biol. Chem., 266, 12866-12872 (1991)), have beenidentified—a constitutive form, cyclooxygenase-1 (COX-1), and aninductive form, cyclooxygenase-2 (COX-2). It is thought that theantiinflammatory effects of NSAIDs are mediated by the inhibition ofCOX-2, whereas the side effects seem to be caused by the inhibition ofCOX-1. The NSAIDs currently on the market either inhibit both isoformsof COX with little selectivity for either isoform or are COX-1selective. Recently compounds that are selective COX-2 inhibitors havebeen developed and marketed. These selective COX-2 inhibitors have thedesired therapeutic profile of an antiinflammatory drug without theadverse effects commonly associated with the inhibition of COX-1.However, these compounds can result in dyspepsia and can causegastropathy (Mohammed et al, N. Engl. J. Med., 340(25) 2005 (1999)).

Selective COX-2 inhibitors are disclosed in, for example, U.S. Pat. Nos.5,681,842, 5,750,558, 5,756,531, 5,776,984 and in WO 97/41100, WO98/39330, WO 99/10331, WO 99/10332 and WO 00/24719 assigned to AbbottLaboratories; and in WO 98/50075, WO 00/29022 and WO 00/29023 assignedto Algos Pharmaceutical Corporation; and in WO 99/15205 assigned toAlmirall Prodesfarma S.A.; and in U.S. Pat. No. 5,980,905 assigned toAMBI Inc.; and in U.S. Pat. No. 5,945,538 assigned to American CyanamidCompany; and in U.S. Pat. Nos. 5,776,967, 5,824,699, 5,830,911 and in WO98/04527 and WO 98/21195 assigned to American Home Products Corporation;and in WO 98/22442 assigned to Angelini Richerche S.P.A. SocietaConsortile; and in U.S. Pat. No. 6,046,191 and in WO 99/18960 and WO00/00200 assigned to Astra Pharmaceuticals Ltd.; and in U.S. Pat. No.5,905,089 assigned to Board of Supervisors of Louisiana StateUniversity; and in WO 97/13767 assigned to Chemisch PharmazeutischeForschungsgesellschaft MBH; and in WO 98/57924 and WO 99/61436 assignedto Chugai Seiyaku Kabushiki Kaisha; and in WO 00/13685 assigned toCornell Research Foundation Inc.; and in WO 96/10021 assigned to The DuPont Merck Pharmaceutical Company; and in EP 0 087 629 B1 assigned toE.I. Du Pont de Nemours and Company; and in WO 99/13799 assigned toEuro-Celtique; and in U.S. Pat. No. 5,134,142 and in WO 91/19708, WO97/13755, WO 99/15505, WO 99/25695 and in EP 0 418 845 B1 and EP 0 554829 A2 assigned to Fujisawa Pharmaceutical Co. Ltd.; and in U.S. Pat.Nos. 5,344,991, 5,393,790, 5,434,178, 5,466,823, 5,486,534, 5,504,215,5,508,426, 5,510,496, 5,516,907, 5,521,207, 5,563,165, 5,580,985,5,596,008, 5,616,601, 5,620,999, 5,633,272, 5,643,933, 5,668,161,5,686,470, 5,696,143, 5,700,816, 5,719,163, 5,753,688, 5,756,530,5,760,068, 5,859,257, 5,908,852, 5,935,990, 5,972,986, 5,985,902,5,990,148, 6,025,353, 6,028,072, 6,136,839 and in WO 94/15932, WO94/27980, WO 95/11883, WO 95/15315, WO 95/15316, WO 95/15317, WO95/15318, WO 95/21817, WO 95/30652, WO 95/30656, WO 96/03392, WO96/03385, WO 96/03387, WO 96/03388, WO 96/09293, WO 96/09304, WO96/16934, WO 96/25405, WO 96/24584, WO 96/24585, WO 96/36617, WO96/38418, WO 96/38442, WO 96/41626, WO 96/41645, WO 97/11704, WO97/27181, WO 97/29776, WO 97/38986, WO 98/06708, WO 98/43649, WO98/47509, WO 98/47890, WO 98/52937, WO 99/22720, WO 00/23433, WO00/37107, WO 00/38730, WO 00/38786 and WO 00/53149 assigned to G.D.Searle & Co.; and in WO 96/31509, WO 99/12930, WO 00/26216 and WO00/52008 assigned to Glaxo Group Limited; and in EP 1 006 114 A1 and inWO 98/46594 assigned to Grelan Pharmaceutical Co. Ltd.; and in WO97/34882 assigned to Grupo Farmaceufico Almirall; and in WO 97/03953assigned to Hafslund Nycomed Pharma AG; and in WO 98/32732 assigned toHoffman-La Roche AG; and in U.S. Pat. Nos. 5,945,539, 5,994,381,6,002,014 and in WO 96/19462, WO 96/19463 and in EP 0 745 596 A1assigned to Japan Tobacco, Inc.; and in U.S. Pat. Nos. 5,686,460,5,807,873 and in WO 97/37984, WO 98/05639, WO 98/11080 and WO 99/21585assigned to Laboratories USPA; and in WO 99/62884 assigned toLaboratories Del Dr. Esteve, S. A.; and in WO 00/08024 assigned toLaboratorios S.A.L.V.A.T., S.A.; and in U.S. Pat. Nos. 5,585,504,5,840,924, 5,883,267, 5,925,631, 6,001,843, 6,080,876 and in WO97/44027, WO 97/44028, WO 97/45420, WO 98/00416, WO 98/47871, WO99/15503, WO 99/15513, WO 99/20110, WO 99/45913, WO 99/55830, WO00/25779 and WO 00/27382 assigned to Merck & Co. Inc.; and in U.S. Pat.Nos. 5,409,944, 5,436,265, 5,474,995, 5,536,752, 5,550,142, 5,510,368,5,521,213, 5,552,422, 5,604,253, 5,604,260, 5,639,780, 5,677,318,5,691,374, 5,698,584, 5,710,140, 5,733,909, 5,789,413, 5,817,700,5,840,746, 5,849,943, 5,861,419, 5,981,576, 5,994,379, 6,020,343,6,071,936, 6,071,954 and in EP 0 788 476 B1, EP 0 863 134 A1, EP 0 882016 B1 and in WO 94/20480, WO 94/13635, WO 94/26731, WO 95/00501, WO95/18799, WO 96/06840, WO 96/13483, WO 96/19469, WO 96/21667, WO96/23786, WO 96/36623, WO 96/37467, WO 96/37468, WO 96/37469, WO97/14691, WO 97/16435, WO 97/28120, WO 97/28121, WO 97/36863, WO98/03484, WO 98/41511, WO 98/41516, WO 98/43966, WO 99/14194, WO99/14195, WO 99/23087, WO 99/41224 and WO 00/68215 assigned to MerckFrosst Canada & Co., and in WO 99/59635 assigned to Merck Sharp & DohmeLimited; and in U.S. Pat. No. 5,380,738 assigned to Monsanto Company;and in WO 00/01380 assigned to A. Nattermann & Co.; and in WO 99/61016assigned to Nippon Shinyaku Co. Ltd.; and in WO 99/33796 assigned toNissin Food Products Co. Ltd.; and in WO 99/11605 assigned to Novartis AG; and in WO 98/33769 assigned to Nycomed Austria GMBH; and in U.S. Pat.Nos. 6,077,869 and 6,083,969 and in WO 00/51685 assigned to Ortho-McNeilPharmaceutical, Inc.; and in U.S. Pat. No. 5,783,597 assigned to OrthoPharmaceutical Corporation; and in WO 98/07714 assigned to OxisInternational Inc.; and in WO 00/10993 assigned to Pacific Corporation;and in EP 0 937 722 A1 and in WO 98/50033, WO 99/05104, WO 99/35130 andWO 99/64415 assigned to Pfizer Inc.; and in WO 00/48583 assigned toPozen Inc.; and in U.S. Pat. No. 5,908,858 assigned to Sankyo CompanyLimited; and in WO 97/25045 assigned to SmithKline Beecham Corporation;and in U.S. Pat. No. 5,399,357 assigned to Takeda Chemical Industries,Ltd.; and in WO 99/20589 assigned to The University of Sydney; and inU.S. Pat. No. 5,475,021 and WO 00/40087 assigned to VanderbiltUniversity; and in WO 99/59634 assigned to Wakamoto Pharmaceutical Co.Ltd., the disclosures of each of which are incorporated by referenceherein in their entirety.

There is still a need in the art for COX-2 inhibitor compounds that havegastroprotective properties, facilitate wound healing, decreased renaltoxicity and dyspepsia, and that can be used at low dosages. The presentinvention is directed to these, as well as other, important ends.

SUMMARY OF THE INVENTION

The present invention provides novel nitrosated and/or nitrosylatedCOX-2 inhibitors, which are COX-2 inhibitors linked to at least onenitrogen monoxide group (NO), and/or at least one nitrogen dioxide group(NO₂) (i.e., nitrosylated and/or nitrosated group, respectively). Theresulting compounds are potent analgesics, have antiinflammatoryproperties and have an unexpected potential for facilitating woundhealing. The novel compounds also have unexpected properties in thetreatment and/or prevention of renal toxicity. The COX-2 inhibitors canbe nitrosated and/or nitrosylated through one or more sites, such asoxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/ornitrogen. The COX-2 inhibitor can be, for example, a sulfonamidecontaining 1,5-diarylpyrazole derivative, such as, for example,CELEBREX®(4-(5-(4methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide,Celecoxib). The COX-2 inhibitor can also be, for example, amethylsulfonylphenyl-furanone derivative, such as, for example,Rofecoxib (VIOXX®,4-(4′-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone). The presentinvention also provides compositions comprising such compounds in apharmaceutically acceptable carrier.

The present invention is also based on the discovery that administeringat least one nitrosated and/or nitrosylated COX-2 inhibitor and at leastone nitric oxide donor reduces the gastrointestinal distress induced byCOX-2 inhibitors. A nitric oxide donor is a compound that contains anitric oxide moiety and which releases or chemically transfers nitricoxide to another molecule. Nitric oxide donors include, for example,S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, andsubstrates of the various isozymes of nitric oxide synthase. Thus,another aspect of the invention provides compositions comprising atleast one COX-2 inhibitor that is substituted with at least one NOand/or NO₂ group (i.e., nitrosylated and/or nitrosated), and at leastone compound that donates, transfers or releases nitric oxide as acharged species, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as theneutral species, nitric oxide (NO•), and/or stimulates endogenousproduction of nitric oxide or EDRF in vivo and/or is a substrate fornitric oxide synthase.

Yet another aspect of the invention provides compositions comprising atleast one COX-2 inhibitor that is substituted with at least one NOand/or NO₂ group (i.e., nitrosylated and/or nitrosated), and,optionally, at least one compound that donates, transfers or releasesnitric oxide as a charged species, i.e., nitrosonium (NO⁺) or nitroxyl(NO−), or as the neutral species, nitric oxide (NO•), and/or stimulatesendogenous production of nitric oxide or EDRF in vivo and/or is asubstrate for nitric oxide synthase, and, optionally, at least onetherapeutic agent, including but not limited to, steroids, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, decongestants, diuretics,sedating or non-sedating anti-histamines, inducible nitric oxidesynthase inhibitors, opioids, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and thelike.

Another aspect of the invention provides compositions comprising atleast one parent COX-2 inhibitor and at least one compound that donates,transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutral species, nitricoxide (NO•), and/or stimulates endogenous production of nitric oxide orEDRF in vivo and/or is a substrate for nitric oxide synthase, and,optionally, at least one therapeutic agent, including but not limitedto, steroids, nonsteroidal antiinflammatory compounds (NSAID),5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HT agonists,HMG CoA inhibitors, H₂ antagonists, antineoplastic agents, antiplateletagents, decongestants, diuretics, sedating or non-sedatinganti-histamines, inducible nitric oxide synthase inhibitors, opioids,analgesics, Helicobacter pylori inhibitors, proton pump inhibitors,isoprostane inhibitors, and the like.

Yet another aspect of the present invention provides methods fortreating and/or preventing inflammation, pain and fever; for treatingand/or improving gastrointestinal properties of COX-2 inhibitors; forfacilitating wound healing; for treating and/or preventing renaltoxicity; and for treating and/or preventing COX-2 mediated disorders(i.e., disorders resulting from elevated levels of COX-2) in a patientin need thereof which comprises administering to the patient atherapeutically effective amount of at least one nitrosated and/ornitrosylated COX-2 inhibitor compound, and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutralspecies, nitric oxide (NO•), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase and/or stimulates endogenous production of NO or EDRF in vivoand/or is a substrate for nitric oxide synthase (i.e., NO donors). Themethod can optionally further comprise the administration of at leastone therapeutic agent, such as, for example, steroids, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, 3hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, decongestants, diuretics, sedating or non-sedatinganti-histamines, inducible nitric oxide synthase inhibitors, opioids,analgesics, Helicobacter pylori inhibitors, proton pump inhibitors,isoprostane inhibitors, and mixtures thereof. In this aspect of theinvention, the methods can involve administering nitrosated and/ornitrosylated COX-2 inhibitors, administering nitrosated and/ornitrosylated COX-2 inhibitors and NO donors, administering nitrosatedand/or nitrosylated COX-2 inhibitors and therapeutic agents, oradministering nitrosated and/or nitrosylated COX-2 inhibitors, NO donorsand therapeutic agents. The nitrosated and/or nitrosylated COX-2inhibitors, nitric oxide donors, and/or therapeutic agents can beadministered separately or as components of the same composition in oneor more pharmaceutically acceptable carriers.

Another aspect of the present invention provides methods for treatinginflammation, pain and fever; for treating and/or improving thegastrointestinal properties of COX-2 inhibitors; for facilitating woundhealing; for treating and/or preventing renal toxicity; and for treatingand/or preventing other cyclooxygenase-2 mediated disorders comprisingadministration of at least one parent COX-2 inhibitor and at least onenitric oxide donor, and, optionally, at least one therapeutic agent.

Yet another aspect of the present invention provides kits comprising atleast one nitrosated and/or nitrosylated COX-2 inhibitor, and,optionally, at least one compound that donates, transfers or releasesnitric oxide as a charged species, i.e., nitrosonium (NO⁺) or nitroxyl(NO−), or as the neutral species, nitric oxide (NO•), and/or stimulatesendogenous production of nitric oxide or EDRF in vivo and/or is asubstrate for nitric oxide synthase. The kit can further comprise atleast one therapeutic agent. The nitrosated and/or nitrosylated COX-2inhibitor, the nitric oxide donor and/or therapeutic agent, can beseparate components in the kit or can be in the form of a composition inone or more pharmaceutically acceptable carriers.

Yet another aspect of the present invention provides kits comprising atleast one parent COX-2 inhibitor and at least one compound that donates,transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutral species, nitricoxide (NO•), and/or stimulates endogenous production of nitric oxide orEDRF in vivo and/or is a substrate for nitric oxide synthase. The kitcan further comprise at least one therapeutic agent. The parent COX-2inhibitor, the nitric oxide donor and/or therapeutic agent, can beseparate components in the kit or can be in the form of a composition inone or more pharmaceutically acceptable carriers.

These and other aspects of the present invention are explained in detailherein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the relaxation of rat aortic smooth muscle rings by (a)isosorbide dinitrate (ISDN, open triangles); (b) Example 1a(non-nitrosated compound, open circles); and (c) Example 1b (nitrosatedcompound, open squares). The non-nitrosated compound of Example 1a didnot relax the tissue. At higher concentrations, the relaxation of thenitrosated compound of Example 1b was similar to that obtained withISDN. Total number of samples tested varied from a minimum of 5 to amaximum of 12. In the x axis, log M corresponds to ten fold increases ofthe test compound from 100 nM (10⁻⁷) to 100 μM (10⁻⁴). Results areexpressed as the mean±standard error of the mean of the percentage oftotal relaxation induced by 10 μM phenylephrine.

FIG. 2 shows the relaxation of rat aortic smooth muscle rings by (a)isosorbide dinitrate (ISDN, open triangles); (b) Example 2a(non-nitrosated compound, open squares); and (c) Example 2b (nitrosatedcompound, open circles). The non-nitrosated compound of Example 2a didnot relax the tissue. At higher concentrations, the relaxation of thenitrosated compound of Example 2b was comparable to that obtained withISDN. Total number of samples tested varied from a minimum of 6 to amaximum of 12. In the x axis, log M corresponds to ten fold increases ofthe test compound from 100 nM (10⁻⁷) to 100 μM (10⁻⁴). Results areexpressed as the mean±standard error of the mean of the percentage oftotal relaxation induced by 10 μM phenylephrine.

FIG. 3 shows the relaxation of rat aortic smooth muscle rings by (a)S-nitrosoglutathione (GSNO, open triangles); (b) Example 3e(non-nitrosylated compound, open squares); and (c) Example 3g(nitrosylated compound, open circles). The non-nitrosylated compound ofExample 3e did not relax the tissue. At higher concentrations, therelaxation of the nitrosylated compound of Example 3g was comparable tothat obtained with GSNO. Total number of samples tested varied from aminimum of 4 to a maximum of 12. In the x axis, log M corresponds to tenfold increases of the test compound from 100 nM (10⁻⁷) to 100 μM (10⁻⁴).Results are expressed as the mean±standard error of the mean of thepercentage of total relaxation induced by 10 μM phenylephrine.

FIG. 4 shows the relaxation of rat aortic smooth muscle rings by (a)isosorbide dinitrate (ISDN, open circles); (b) Example 20c(non-nitrosated compound, open inverted triangles); and (c) Example 20d(nitrosated compound, open squares). The non-nitrosated compound ofExample 20c did not relax the tissue. At higher concentrations, therelaxation of the nitrosated compound of Example 20d was comparable tothat obtained with ISDN. Total number of samples tested varied from aminimum of 4 to a maximum of 16. In the x axis, log M corresponds to tenfold increases of the test compound from 100 nM (10⁻⁷) to 100 μM (10⁻⁴).Results are expressed as the mean±standard error of the mean of thepercentage of total relaxation induced by 10 μM phenylephrine.

FIG. 5 shows that anti-inflammatory effect of (a) Celecoxib (open bars);(b) Example 2a (non-nitrosated compound, horizontal stripped bars); and(c) Example 2b (nitrosated compound, hatched bars) using thecarrageenan-induced paw edema test. Total samples, 5 for eachconcentration of test compound. The x axis corresponds to the dose ofthe test compounds in μmol/kg body weight of the rats. The y axiscorresponds to the increase in the paw volume (mL). Results areexpressed as the mean±standard error of the change in paw volume. Datawas analyzed by AVONA analysis followed by Student Newmann-Keulspost-hoc test.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout the disclosure, the following terms, unless otherwiseindicated, shall be understood to have the following meanings.

“NSAID” refers to a nonsteroidal anti-inflammatory compound or anonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, theenzyme responsible for the biosyntheses of the prostaglandins andcertain autocoid inhibitors, including inhibitors of the variousisozymes of cyclooxygenase (including but not limited tocyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase andlipoxygenase.

“Cyclooxygenase-2 (COX-2) inhibitor” refers to a compound thatselectively inhibits the cyclooxygenase-2 enzyme over thecyclooxygenase-1 enzyme. Preferably, the compound has a cyclooxygenase-2IC₅₀ of less than about 0.5 μM, and also has a selectivity ratio ofcyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least50, and more preferably of at least 100. Even more preferably, thecompound has a cyclooxygenase-1 IC₅₀ of greater than about 1 μM, andmore preferably of greater than 20 μM. The compound can also inhibit theenzyme, lipoxygenase and/or phosphodiestase. Such preferred selectivitymay indicate an ability to reduce the incidence of common NSAID-inducedside effects.

“Parent COX-2 inhibitor” refers to a non-nitrosated and/ornon-nitrosylated COX-2 inhibitor and includes those described in theprior art, including those described in the patents and publicationscited herein, as well as the novel compounds described herein. “ParentCOX-2 inhibitor” includes the compounds of formulas I to XVI before theyare nitrosated and/or nitrosylated by the methods described herein.

“Therapeutic agent” includes any therapeutic agent that can be used totreat or prevent the diseases described herein. “Therapeutic agents”include, for example, steroids, nonsteroidal antiinflammatory compounds,5-lipoxygenase inhibitors, leukotriene B₄ receptor antagonists,leukotriene A₄ hydrolase inhibitors, 5-HT agonists,3-hydroxy-3-methylglutaryl coenzyme A inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, decongestants, diuretics,sedating or non-sedating anti-histamines, inducible nitric oxidesynthase inhibitors, opioids, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and thelike. Although NO donors have therapeutic activity, the term“therapeutic agent” does not include the NO donors described herein,since NO donors are separately defined.

“Patient” refers to animals, preferably mammals, most preferably humans,and includes males and females, and children and adults.

“Therapeutically effective amount” refers to the amount of the compoundand/or composition that is effective to achieve its intended purpose.

“Transdermal” refers to the delivery of a compound by passage throughthe skin and into the blood stream.

“Transmucosal” refers to delivery of a compound by passage of thecompound through the mucosal tissue and into the blood stream.

“Penetration enhancement” or “permeation enhancement” refers to anincrease in the permeability of the skin or mucosal tissue to a selectedpharmacologically active compound such that the rate at which thecompound permeates through the skin or mucosal tissue is increased.

“Carriers” or “vehicles” refers to carrier materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not interactwith any components of the composition in a deleterious manner.

“Nitric oxide adduct” or “NO adduct” refers to compounds and functionalgroups which, under physiological conditions, can donate, release and/ordirectly or indirectly transfer any of the three redox forms of nitrogenmonoxide (NO⁺, NO⁻, NO•), such that the biological activity of thenitrogen monoxide species is expressed at the intended site of action.

“Nitric oxide releasing” or “nitric oxide donating” refers to methods ofdonating, releasing and/or directly or indirectly transferring any ofthe three redox forms of nitrogen monoxide (NO⁺, NO⁻, NO•), such thatthe biological activity of the nitrogen monoxide species is expressed atthe intended site of action.

“Nitric oxide donor” or “NO donor” refers to compounds that donate,release and/or directly or indirectly transfer a nitrogen monoxidespecies, and/or stimulate the endogenous production of nitric oxide orendothelium-derived relaxing factor (EDRF) in vivo and/or elevateendogenous levels of nitric oxide or EDRF in vivo. “NO donor” alsoincludes compounds that are substrates for nitric oxide synthase.

“Alkyl” refers to a lower alkyl group, a haloalkyl group, a hydroxyalkylgroup, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, acycloalkyl group or a heterocyclic ring, as defined herein. An alkylgroup may also comprise one or more radical species, such as, forexample a cycloalkylalkyl group or a heterocyclicalkyl group.

“Lower alkyl” refers to a branched or straight chain acyclic alkyl groupcomprising one to about ten carbon atoms (preferably one to about eightcarbon atoms, more preferably one to about six carbon atoms). Exemplarylower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl,and the like.

“Substituted lower alkyl” refers to a lower alkyl group, as definedherein, wherein one or more of the hydrogen atoms have been replacedwith one or more R¹⁰⁰ groups, wherein each R¹⁰⁰ is independently ahydroxy, an oxo, a carboxyl, a carboxamido, a halo, a cyano or an aminogroup, as defined herein.

“Haloalkyl” refers to a lower alkyl group, an alkenyl group, an alkynylgroup, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclicring, as defined herein, to which is appended one or more halogens, asdefined herein. Exemplary haloalkyl groups include trifluoromethyl,chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the like.

“Alkenyl” refers to a branched or straight chain C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon double bonds. Exemplaryalkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl,2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, hepten-1-yl,octen-1-yl, and the like.

“Lower alkenyl” refers to a branched or straight chain C₂-C₄ hydrocarbonwhich can comprise one or two carbon-carbon double bonds.

“Substituted alkenyl” refers to a branched or straight chain C₂-C₁₀hydrocarbon (preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆hydrocarbon) which can comprise one or more carbon-carbon double bonds,wherein one or more of the hydrogen atoms have been replaced with one ormore R¹⁰⁰ groups, wherein each R¹⁰⁰ is independently a hydroxy, an oxo,a carboxyl, a carboxamido, a halo, a cyano or an amino group, as definedherein.

“Alkynyl” refers to an unsaturated acyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds. Exemplaryalkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl,pentyl-1-yl, pentyl-2-yl, 3methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl,hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like.

“Bridged cycloalkyl” refers to two or more cycloalkyl groups,heterocyclic groups, or a combination thereof fused via adjacent ornon-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridgedcycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl,2,6-dioxabicyclo[3.3.0]octane, 7-oxabycyclo[2.2.1]heptyl,8-azabicyclo[3,2,1]oct-2-enyl and the like.

“Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarboncomprising from about 3 to about 10 carbon atoms. Cycloalkyl groups canbe unsubstituted or substituted with one, two or three substituentsindependently selected from alkyl, alkoxy, amino, alkylamino,dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl,ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo, alkylsulfinyl, and nitro.Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta,1,3dienyl, and thelike.

“Heterocyclic ring or group” refers to a saturated or unsaturated cyclichydrocarbon group having about 2 to about 10 carbon atoms (preferablyabout 4 to about 6 carbon atoms) where 1 to about 4 carbon atoms arereplaced by one or more nitrogen, oxygen and/or sulfur atoms. Sulfurmaybe in the thio, sulfinyl or sulfonyl oxidation state. Theheterocyclic ring or group can be fused to an aromatic hydrocarbongroup. Heterocyclic groups can be unsubstituted or substituted with one,two or three substituents independently selected from alkyl, alkoxy,amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thial,halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylicester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester,alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido,alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary heterocyclic groups include pyrrolyl,3pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4-dihydropyridinyl,pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl,imidazolyl, indolyl, thiophenyl, furanyl, tetrhydrofuranyl, tetrazolyl,pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, imidazolinyl,imidazolindinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl,4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl,1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, benzothiazolinyl,quinolinyl, and the like.

“Heterocyclic compounds” refer to mono- and polycyclic compoundscomprising at least one aryl or heterocyclic ring.

“Aryl” refers to a monocyclic, bicyclic, carbocyclic or heterocyclicring system comprising one or two aromatic rings. Exemplary aryl groupsinclude phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl,indanyl, indenyl, indoyl, and the like. Aryl groups (including bicyclicaryl groups) can be unsubstituted or substituted with one, two or threesubstituents independently selected from alkyl, alkoxy, alkylthio,amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino,halo, cyano, alkylsulfinyl, hydroxy, carboxyl, carboxylic ester,alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid,arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester,carboxamido, alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary substituted aryl groups includetetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl,arylsulfonyl, and the like.

“Cycloalkenyl” refers to an unsaturated cyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds.

“Arylalkyl” refers to an aryl radical, as defined herein, attached to analkyl radical, as defined herein. Exemplary arylalkyl groups includebenzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl,2-fluorophenylethyl, and the like.

“Arylalkenyl” refers to an aryl radical, as defined herein, attached toan alkenyl radical, as defined herein. Exemplary arylalkenyl groupsinclude styryl, propenylphenyl, and the like.

“Cycloalkylalkyl” refers to a cycloalkyl radical, as defined herein,attached to an alkyl radical, as defined herein.

“Cycloalkylalkoxy” refers to a cycloalkyl radical, as defined herein,attached to an alkoxy radical, as defined herein.

“Cycloalkylalkylthio” refers to a cycloalkyl radical, as defined herein,attached to an alkylthio radical, as defined herein.

“Heterocyclicalkyl” refers to a heterocyclic ring radical, as definedherein, attached to an alkyl radical, as defined herein.

“Arylheterocyclic ring” refers to a bi- or tricyclic ring comprised ofan aryl ring, as defined herein, appended via two adjacent carbon atomsof the aryl ring to a heterocyclic ring, as defined herein. Exemplaryarylheterocyclic rings include dihydroindole,1,2,3,4tetra-hydroquinoline, and the like.

“Alkoxy” refers to R₅₀O—, wherein R₅₀ is an alkyl group, as definedherein (preferably a lower alkyl group or a haloalkyl group, as definedherein). Exemplary alkoxy groups include methoxy, ethoxy, t-butoxy,cyclopentyloxy, trifluoromethoxy, and the like.

“Aryloxy” refers to R₅₅O—, wherein R₅₅ is an aryl group, as definedherein. Exemplary aryloxy groups include napthyloxy, quinolyloxy,isoquinolizinyloxy, and the like.

“Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, as definedherein.

“Arylalkoxy or alkoxyaryl” refers to an alkoxy group, as defined herein,to which is appended an aryl group, as defined herein. Exemplaryarylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy,and the like.

“Alkoxyalkyl” refers to an alkoxy group, as defined herein, appended toan alkyl group, as defined herein. Exemplary alkoxyalkyl groups includemethoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

“Alkoxyhaloalkyl” refers to an alkoxy group, as defined herein, appendedto a haloalkyl group, as defined herein. Exemplary alkoxyhaloalkylgroups include 4-methoxy-2-chlorobutyl and the like.

“Cycloalkoxy” refers to R₅₄O—, wherein R₅₄ is a cycloalkyl group or abridged cycloalkyl group, as defined herein. Exemplary cycloalkoxygroups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

“Cycloalkylthio” refers to R₅₄S—, wherein R₅₄ is a cycloalkyl group or abridged cycloalkyl group, as defined herein. Exemplary cycloalkylthiogroups include cyclopropylthio, cyclopentylthio, cyclohexylthio, and thelike.

“Haloalkoxy” refers to an alkoxy group, as defined herein, in which oneor more of the hydrogen atoms on the alkoxy group are substituted withhalogens, as defined herein. Exemplary haloalkoxy groups include1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.

“Hydroxy” refers to —OH.

“Oxo” refers to ═O.

“Oxy” refers to —O⁻R₇₇ ⁺ wherein R₇₇ is an organic or inorganic cation.

“Organic cation” refers to a positively charged organic ion. Exemplaryorganic cations include alkyl substituted ammonium cations, and thelike.

“Inorganic cation” refers to a positively charged metal ion. Exemplaryinorganic cations include Group I metal cations such as for example,sodium, potassium, and the like.

“Hydroxyalkyl” refers to a hydroxy group, as defined herein, appended toan alkyl group, as defined herein.

“Nitrate” refers to —O—NO₂.

“Nitrite” refers to —O—NO.

“Thionitrate” refers to —S—NO₂.

“Thionitrite” and “nitrosothiol” refer to —S—NO.

“Nitro” refers to the group —NO₂ and “nitrosated” refers to compoundsthat have been substituted therewith.

“Nitroso” refers to the group —NO and “nitrosylated” refers to compoundsthat have been substituted therewith.

“Nitrile” and “cyano” refer to —CN.

“Halogen” or “halo” refers to iodine (I), bromine (Br), chlorine (Cl),and/or fluorine (F).

“Amino” refers to —NH₂, an alkylamino group, a dialkylamino group, anarylamino group, a diarylamino group, an alkylarylamino group or aheterocyclic ring, as defined herein.

“Alkylamino” refers to R₅₀NH—, wherein R₅₀ is an alkyl group, as definedherein. Exemplary alkylamino groups include methylamino, ethylamino,butylamino, cyclohexylamino, and the like.

“Arylamino” refers to R₅₅NH—, wherein R₅₅ is an aryl group, as definedherein.

“Dialkylamino” refers to R₅₂R₅₃N—, wherein R₅₂ and R₅₃ are eachindependently an alkyl group, as defined herein. Exemplary dialkylaminogroups include dimethylamino, diethylamino, methyl propargylamino, andthe like.

“Diarylamino” refers to R₅₅R₆₀N—, wherein R₅₅ and R₆₀ are eachindependently an aryl group, as defined herein.

“Alkylarylamino or arylalkylamino” refers to R₅₂R₅₅N—, wherein R₅₂ is analkyl group, as defined herein, and R₅₅ is an aryl group, as definedherein.

“Alkylarylalkylamino” refers to R₅₂R₇₉N—, wherein R₅₂ is an alkyl group,as defined herein, and R₇₉ is an arylalkyl group, as defined herein.

“Alkylcycloalkylamino” refers to R₅₂R₈₀N—, wherein R₅₂ is an alkylgroup, as defined herein, and R₈₀ is an cycloalkyl group, as definedherein.

“Aminoalkyl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an alkyl group, as defined herein. Exemplary aminoalkylgroups include dimethylaminopropyl, diphenylaminocyclopentyl,methylaminomethyl, and the like.

“Aminoaryl” refers to an aryl group to which is appended an alkylaminogroup, a arylamino group or an arylalkylamino group. Exemplary aminoarylgroups include anilino, N-methylanilino, N-benzylanilino, and the like.

“Thio” refers to —S—.

“Sulfinyl” refers to —S(O)—.

“Methanthial” refers to —C(S)—.

“Thial” refers to ═S.

“Sulfonyl” refers to —S(O)₂ ⁻.

“Sulfonic acid” refers to —S(O)₂OR₇₆, wherein R₇₆ is a hydrogen, anorganic cation or an inorganic cation, as defined herein.

“Alkylsulfonic acid” refers to a sulfonic acid group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonic acid” refers to an sulfonic acid group, as defined herein,appended to an aryl group, as defined herein.

“Sulfonic ester” refers to —S(O)₂OR₅₈, wherein R₅₈ is an alkyl group, anaryl group or an aryl heterocyclic ring, as defined herein.

“Sulfonamido” refers to —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

“Alkylsulfonamido” refers to a sulfonamido group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonamido” refers to a sulfonamido group, as defined herein,appended to an aryl group, as defined herein.

“Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, as definedherein (preferably a lower alkyl group, as defined herein).

“Arylthio” refers to R₅₅S—, wherein R₅₅ is an aryl group, as definedherein.

“Arylalkylthio” refers to an aryl group, as defined herein, appended toan alkylthio group, as defined herein.

“Alkylsulfinyl” refers to R₅₀—S(O)—, wherein R₅₀ is an alkyl group, asdefined herein.

“Alkylsulfonyl” refers to R₅₀—S(O)₂—, wherein R₅₀ is an alkyl group, asdefined herein.

“Alkylsulfonyloxy” refers to R₅₀—S(O)₂—O—, wherein R₅₀ is an alkylgroup, as defined herein.

“Arylsulfinyl” refers to R₅₅—S(O)—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylsulfonyl” refers to R₅₅—S(O)₂—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylsulfonyloxy” refers to R₅₅—S(O)₂—O—, wherein R₅₅ is an aryl group,as defined herein.

“Amidyl” refers to R₅₁C(O)N(R₅₇)— wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein.

“Ester” refers to R₅₁C(O)O— wherein R₅₁ is a hydrogen atom, an alkylgroup, an aryl group or an arylheterocyclic ring, as defined herein.

“Carbamoyl” refers to —O—C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ taken togetherare a heterocyclic ring, a cycloalkyl group or a bridged cycloalkylgroup, as defined herein.

“Carboxyl” refers to —C(O)OR₇₆, wherein R₇₆ is a hydrogen, an organiccation or an inorganic cation, as defined herein.

“Carbonyl” refers to —C(O)—.

“Alkylcarbonyl” refers to R₅₂—C(O)—, wherein R₅₂ is an alkyl group, asdefined herein.

“Arylcarbonyl” refers to R₅₅—C(O)—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylalkylcarbonyl” refers to R₅₅—R₅₂—C(O)—, wherein R₅₅ is an arylgroup, as defined herein, and R₅₂ is an alkyl group, as defined herein.

“Alkylarylcarbonyl” refers to R₅₂—R₅₅—C(O)—, wherein R₅₅ is an arylgroup, as defined herein, and R₅₂ is an alkyl group, as defined herein.

“Heterocyclicalkylcarbonyl” refer to R₇₈C(O)— wherein R₇₈ is aheterocyclicalkyl group, as defined herein.

“Carboxylic ester” refers to —C(O)OR₅₈, wherein R₅₈ is an alkyl group,an aryl group or an aryl heterocyclic ring, as defined herein.

“Alkylcarboxylic acid” and “alkylcarboxyl” refer to an alkyl group, asdefined herein, appended to a carboxyl group, as defined herein.

“Alkylcarboxylic ester” refers to an alkyl group, as defined herein,appended to a carboxylic ester group, as defined herein.

“Arylcarboxylic acid” refers to an aryl group, as defined herein,appended to a carboxyl group, as defined herein.

“Arylcarboxylic ester” and “arylcarboxyl” refer to an aryl group, asdefined herein, appended to a carboxylic ester group, as defined herein.

“Carboxamido” refers to —C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

“Alkylcarboxamido” refers to an alkyl group, as defined herein, appendedto a carboxamido group, as defined herein.

“Arylcarboxamido” refers to an aryl group, as defined herein, appendedto a carboxamido group, as defined herein.

“Urea” refers to —N(R₅₉)—C(O)N(R₅₁)(R₅₇) wherein R₅₁, R₅₇, and R₅₉ areeach independently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ taken togetherare a heterocyclic ring, a cycloalkyl group or a bridged cycloalkylgroup, as defined herein.

“Phosphoryl” refers to —P(R₇₀)(R₇₁)(R₇₂), wherein R₇₀ is a lone pair ofelectrons, thial or oxo, and R₇₁ and R₇₂ are each independently acovalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, ahydroxy, an oxy or an aryl, as defined herein.

“Silyl” refers to —Si(R₇₃)(R₇₄)(R₇₅), wherein R₇₃, R₇₄ and R₇₅ are eachindependently a covalent bond, a lower alkyl, an alkoxy, an aryl or anarylalkoxy, as defined herein.

Compounds that donate, transfer or release nitric oxide species in vivohave been recognized as having a wide spectrum of advantages andapplications. The present invention is based on the unexpected discoveryof the effects of such compounds alone and together with one or moreCOX-2 inhibitors directly or indirectly linked with one or more nitricoxide moieties. Treatment or prevention of inflammation, pain and fever;treatment and/or improvement of the gastrointestinal properties of COX-2inhibitors; facilitation of wound healing; and treatment and/orprevention of renal toxicity and cyclooxygenase-2 mediated disorders canbe obtained by the use of the nitrosated and/or nitrosylated COX-2inhibitors of the present invention; or by the use of the nitrosatedand/or nitrosylated COX-2 inhibitors in conjunction with one or morecompounds that donate, release or transfer nitric oxide and/or stimulateendogenous production of NO and/or EDRF in vivo and/or is a substratefor nitric oxide synthase, and, optionally, with one or more therapeuticagents.

In one embodiment, the present invention describes nitrosated and/ornitrosylated COX-2 inhibitors of Formula (I):

wherein:

when side b is a double bond, and sides a and c are single bonds,—X¹—Y¹—Z¹— is:

(a) —CR⁴(R⁵)—CR⁵(R⁵′)—CR⁴(R⁵)—;

(b) —C(O)—CR⁴(R⁴′)—CR⁵(R⁵′)—;

(c) —CR⁴(R⁴′)—CR⁵(R⁵′)—C(O)—;

(d) —(CR⁵(R⁵′))_(k)—O—C(O)—;

(e) —C(O)—O—(CR⁵(R⁵′))_(k)—;

(f) —CR⁴(R⁴′)—NR³—CR⁵(R⁵′)—;

(g) —CR⁵(R⁵′)—NR³—C(O)—;

(h) —CR⁴═CR⁴′—S—;

(i) —S—CR⁴═CR⁴′—;

(j) —S—N═CR⁴—;

(k) —CR⁴═N—S—;

(l) —N═CR⁴—O—;

(m) —O—CR⁴═N—;

(n) —NR³—CR⁴═N—;

(o) —N═CR⁴—S—;

(p) —S—CR⁴═N—;

(q) —C(O)—NR³—CR⁵′(R⁵′)—;

(r) —R³N—CR⁵═C R⁵′—;

(s) —CR⁴═CR⁵—NR³—;

(t) —O—N═CR⁴—;

(u) —CR═N—O—;

(v) —N═N—S—;

(w) —S—N═N—;

(x) —R³N—CR⁴═N—;

(y) —N═CR⁴—NR³—;

(z) —R³N—N═N—;

(aa) —N═N—NR³—;

(bb) —CR⁴(R^(4′))—O—CR⁵(R⁵′)—;

(cc) —CR⁴(R^(4′))—S—CR⁵(R⁵′)—;

(dd) —CR⁴(R^(4′))—C(O)—CR⁵(R⁵′)—;

(ee) —CR⁴(R^(4′))—CR⁵(R⁵′)—C(S)—;

(ff) —(CR⁵(R⁵′))_(k)—O—C(S)—;

(gg) —C(S)—O—(CR⁵(R⁵′))_(k)—;

(hh) —(CR⁵(R⁵′))_(k)—NR³—C(S)—;

(ii) —C(S)—NR³—(CR⁵(R⁵′))_(k)—;

(jj) —(CR⁵(R⁵′))_(k)—S—C(O)—;

(kk) —C(O)—S—(CR⁵(R⁵′))_(k)—;

(ll) —O—CR═CR⁵—;

(mm) —CR⁴═CR—O—;

(nn) —C(O)—NR³—S—;

(oo) —S—NR³—C(O)—;

(pp) —C(O)—NR³—O—;

(qq) —O—NR³—C(O)—;

(rr) —NR³—CR⁴═CR⁵—;

(ss) —CR⁴═N—NR³—;

(tt) —NR³—N═CR⁴—;

(uu) —C(O)—NR—NR³—;

(vv) —NR³—NR³—C(O)—;

(ww) —C(O)—O—NR³—;

(xx) —NR³—O—C(O)—;

(yy) —CR⁴R^(4′)—CR⁵R^(5′);

(zz) —C(O)—CR⁴R^(4′)—

(aaa) —CR⁴R^(4′)—C(O)—;

(bbb) —C(S)—CR⁴R^(4′)—;

(ccc) —CR⁴R^(4′)—C(S)—;

(ddd) —C(═NR³)—CR⁴R^(4′)—; or

(eee) —CR⁴R^(4′)—C(═NR³)—;

when sides a and c are double bonds and side b is a single bond,—X¹—Y¹—Z¹— is:

(a) ═CR⁴—O—CR⁵═;

(b) ═CR⁴—NR³—CR⁵═;

(c) ═N—S—CR⁴═;

(d) ═CR⁴—S—N═;

(e) ═N—O—CR⁴═;

(f) ═CR⁴—O—N═;

(g) ═N—S—N═;

(h) ═N—O—N═;

(i) ═N—NR³—CR⁴═;

(j) ═CR⁴—NR³—N═;

(k) ═N—NR³—N═;

(l) ═CR⁴—S—CR⁵═; or

(m) ═CR⁴—CR⁴(R^(4′))—CR⁵═;

R¹ is:

(a) —S(O)₂—CH₃;

(b) —S(O)₂—NR⁸(D¹);

(c) —S(O)₂—N(D¹)—C(O)—CF₃;

(d) —S(O)—(NH)—NH(D¹);

(e) —S(O)—(NH)—N(D¹)—C(O)—CF₃;

(f) —P(O)(CH₃)NH(D¹);

(g) —P(O)(CH₃)₂;

(h) —C(S)—NH(D¹);

(i) —S(O)(NH)CH₃;

(j) —P(O)(CH₃)OD¹; or

(k) —P(O)(CH₃)NH(D¹);

R^(1′) is:

(a) hydrogen;

(b) halogen;

(c) methyl; or

(d) CH₂OH;

R² is:

(a) lower alkyl;

(b) cycloalkyl;

(c) mono-, di- or tri-substituted phenyl or naphthyl, wherein thesubstituents are each independently:

(1) hydrogen;

(2) halo;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF₃;

(7) lower alkyl;

(8) N₃;

(9) —CO₂D¹;

(10) —CO₂-lower alkyl;

(11) —(C(R⁵)(R⁶))_(z)—OD¹;

(12) —(C(R⁵)(R⁶))—O-lower alkyl;

(13) lower alkyl—CO₂—R⁵;

(14) —OD¹;

(15) haloalkoxy;

(16) amino;

(17) nitro;

(18) alkylsulfinyl; or

(19) heteroaryl;

(d) mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl isa monocyclic aromatic ring of 5 atoms, said ring having one heteroatomwhich is S, O, or N, and, optionally, 1, 2, or 3 additional N atoms; orthe heteroaryl is a monocyclic ring of 6 atoms, said ring having oneheteroatom which is N, and, optionally, 1, 2,3, or 4 additional N atoms;wherein the substituents are each independently:

(1) hydrogen;

(2) halo;

(3) lower alkyl;

(4) alkoxy;

(5) alkylthio;

(6) CN;

(7) haloalkyl, preferably CF₃;

(8) N₃;

(9) —C(R⁵)(R⁶)—OD¹;

(10) —C(R⁵)(R⁶)—O-lower alkyl; or

(11) alkylsulfinyl;

(e) benzoheteroaryl which includes the benzo fused analogs of (d);

(f) —NR¹⁰R¹¹;

(g) —SR¹¹;

(h) —OR¹¹;

(i) —R¹¹;

(j) alkenyl;

(k) alkynyl;

(l) unsubstituted, mono-, di-, tri- or tetra-substituted cycloalkenyl,wherein the substituents are each independently:

(1) halo;

(2) alkoxy;

(3) alkylthio;

(4) CN;

(5) haloalkyl, preferably CF₃;

(6) lower alkyl;

(7) N₃;

(8) —CO₂D¹;

(9) —CO₂-lower alkyl;

(10) —C(R¹²)(R¹³)—OD¹;

(11) —C(R¹²)(R¹³)—O-lower alkyl;

(12) lower alkyl—CO₂—R¹²;

(13) benzyloxy;

(14) —O—(lower alkyl)—CO₂R¹²;

(15) —O—(lower alkyl)—NR¹²R¹³; or

(16) alkylsulfinyl;

(m) mono, di-, tri- or tetra-substituted heterocycloalkyl group of 5, 6or 7 members, or a benzoheterocycle, wherein said heterocycloalkyl orbenzoheterocycle contains 1 or 2 heteroatoms selected from O, S, or Nand, optionally, contains a carbonyl group or a sulfonyl group, andwherein said substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF₃;

(7) N₃;

(8) —C(R¹²)(R¹³)—OD¹;

(9) —C(R¹²)(R¹³)—O-lower alkyl; or

(10) alkylsulfinyl;

(n) styryl, mono or di-substituted styryl, wherein the substituent areeach independently:

(1) halo;

(2) alkoxy;

(3) alkylthio;

(4) CN;

(5) haloalkyl, preferably CF₃;

(6) lower alkyl;

(7) N₃;

(8) —CO₂D¹;

(9) —CO₂-lower alkyl;

(10) —C(R¹²)(R¹³)—OD¹;

(11) —C(R¹²)(R¹³)—O-lower alkyl;

(12) lower alkyl—CO₂—R¹²;

(13) benzyloxy;

(14) —O-(lower alkyl)—CO₂R¹²; or

(15) —O-(lower alkyl)—NR¹²R¹³;

(o) phenylacetylene, mono- or di-substituted phenylacetylene, whereinthe substituents are each independently:

(1) halo;

(2) alkoxy;

(3) alkylthio;

(4) CN;

(5) haloalkyl, preferably CF₃;

(6) lower alkyl;

(7) N₃;

(8) —CO₂D¹;

(9) —CO₂-lower alkyl;

(10) —C(R¹²)(R¹³)—OD¹;

(11) —C(R¹²)(R¹³)—O-lower alkyl;

(12) lower alkyl—CO₂—R¹²;

(13) benzyloxy;

(14) —O-(lower alkyl)—CO₂R¹²; or

(15) —O-(lower alkyl)—NR¹²R¹³;

(p) fluoroalkenyl;

(q) mono- or di-substituted bicyclic heteroaryl of 8, 9 or 10 members,containing 2, 3, 4 or 5 heteroatoms, wherein at least one heteroatomresides on each ring of said bicyclic heteroaryl, said heteroatoms areeach independently O, S and N and said substituents are eachindependently:

(1) hydrogen;

(2) halo;

(3) lower alkyl;

(4) alkoxy;

(5) alkylthio;

(6) CN;

(7) haloalkyl, preferably CF₃;

(8) N₃;

(9) —C(R⁵)(R⁶)—OD¹; or

(10) —C(R⁵)(R⁶)—O-lower alkyl;

(r) K;

(s) aryl;

(t) arylalkyl;

(u) cycloalkylalkyl;

(v) —C(O)R¹¹;

(u) hydrogen;

(v) arylalkenyl;

(w) arylalkoxy;

(x) alkoxy;

(y) aryloxy;

(z) cycloalkoxy;

(aa) arylthio;

(bb) alkylthio;

(cc) arylalkylthio; or

(dd) cycloalkylthio;

R³ is:

(a) hydrogen;

(b) haloalkyl, preferably CF₃;

(c) CN;

(d) lower alkyl;

(e) —(C(R_(e))(R_(f)))_(p)—U—V;

(f) K;

(g) unsubstituted or substituted:

(1) lower alkyl-Q;

(2) lower alkyl-O-lower alkyl-Q;

(3) lower alkyl-S-lower alkyl-Q;

(4) lower alkyl-O—Q;

(5) lower alkyl-S—Q;

(6) lower alkyl-O—V;

(7) lower alkyl-S—V;

(8) lower alkyl-O—K; or

(9) lower alkyl-S—K;

wherein the substituent(s) reside on the lower alkyl group;

(h) Q;

(i) alkylcarbonyl;

(j) arylcarbonyl;

(k) alkylarylcarbonyl;

(l) arylalkylcarbonyl;

(m) carboxylic ester;

(n) carboxamido;

(o) cycloalkyl;

(p) mono-, di- or tri-substituted phenyl or naphthyl, wherein thesubstituents are each independently:

(1) hydrogen;

(2) halo;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF₃;

(7) lower alkyl;

(8) N₃;

(9) —CO₂D¹;

(10) —CO₂-lower alkyl;

(11) —(C(R⁵)(R⁶))_(z)—OD¹;

(12) —(C(R⁵)(R⁶))_(z)—O-lower alkyl;

(13) lower alkyl-CO₂—R⁵;

(14) —OD¹;

(15) haloalkoxy;

(16) amino;

(17) nitro; or

(18) alkylsulfinyl;

(q) alkenyl;

(r) alkynyl;

(s) arylalkyl;

(t) lower alkyl-OD¹;

(u) alkoxyalkyl;

(v) aminoalkyl;

(w) lower alkyl-CO₂R¹⁰;

(x) lower alkyl-C(O)NR¹⁰(R^(10′));

(y) heterocyclicalkyl; or

(z) heterocyclic ring-C(O)—;

R⁴, R⁴′, R⁵ and R⁵′ are each independently:

(a) hydrogen;

(b) amino;

(c) CN;

(d) lower alkyl;

(e) haloalkyl;

(f) alkoxy;

(g) alkylthio;

(h) Q;

(i) —O—Q;

(j) —S—Q;

(k) K;

(l) cycloalkoxy;

(m) cycloalkylthio;

(n) unsubstituted, mono-, or di-substituted phenyl or unsubstituted,mono-, or di-substituted benzyl, wherein the substituents are eachindependently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF₃;

(7) N₃;

(8) Q;

(9) nitro; or

(10) amino;

(o) unsubstituted, mono-, or di-substituted heteroaryl or unsubstituted,mono-, or di-substituted heteroarylmethyl, wherein the heteroaryl is amonocyclic aromatic ring of 5 atoms, said ring having one heteroatomwhich is S, O, or N, and, optionally, 1, 2, or 3 additional N atoms; orthe heteroaryl is a monocyclic ring of 6 atoms, said ring having oneheteroatom which is N, and, optionally, 1, 2, 3, or 4 additional Natoms; said substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF₃;

(7) N₃;

(8) —C(R⁶)(R⁷)—OD¹;

(9) —C(R⁶)(R⁷)—O-lower alkyl; or

(10) alkylsulfinyl

(p) —CON(R⁸)(R⁸);

(q) —CH₂OR⁸;

(r) —CH₂OCN;

(s) unsubstituted or substituted:

(1) lower alkyl-Q;

(2) —O-lower alkyl-Q;

(3) —S-lower alkyl-Q;

(4) lower alkyl-O-lower alkyl-Q;

(5) lower alkyl-S-lower alkyl-Q;

(6) lower alkyl-O—Q;

(7) lower alkyl-S—Q;

(8) lower alkyl-O—K;

(9) lower alkyl-S—K;

(10) lower alkyl-O—V; or

(11) lower alkyl-S—V;

wherein the substituent(s) resides on the lower alkyl;

(t) cycloalkyl;

(u) aryl;

(v) arylalkyl;

(w) cycloalkylalkyl;

(x) aryloxy;

(y) arylalkoxy;

(z) arylalkylthio;

(aa) cycloalkylalkoxy;

(bb) heterocycloalkyl;

(cc) alkylsulfonyloxy;

(dd) alkylsulfonyl;

(ee) arylsulfonyl;

(ff) arylsulfonyloxy;

(gg) —C(O)R¹⁰;

(hh) nitro;

(ii) amino;

(jj) aminoalkyl;

(kk) —C(O)-alkyl-heterocyclic ring;

(ll) halo;

(mm) heterocyclic ring;

(nn) —CO₂D¹;

(oo) carboxyl;

(pp) amidyl; or

(qq) alkoxyalkyl;

alternatively, R⁴ and R⁵ together with the carbons to which they areattached are:

(a) cycloalkyl;

(b) aryl;or

(c) heterocyclic ring;

alternatively, R⁴ and R^(4′) or R⁵ and R^(5′) taken together with thecarbon to which they are attached are:

(a) cycloalkyl; or

(b) heterocyclic ring;

alternatively, R⁴ and R⁵, R^(4′) and R^(5′), R⁴ and R^(5′), or R^(4′)and R⁵ when substituents on adjacent carbon atoms taken together withthe carbons to which they are attached are:

(a) cycloalkyl;

(b) heterocyclic ring; or

(c) aryl;

R⁶ and R⁷ are each independently:

(a) hydrogen;

(b) unsubstituted, mono- or di-substituted phenyl; unsubstituted, mono-or di-substituted benzyl; unsubstituted, mono- or di-substitutedheteroaryl; mono- or di-substituted heteroarylmethyl, wherein saidsubstituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF₃;

(7) N₃;

(8) —C(R¹⁴)(R¹⁵)—OD¹; or

(9) —C(R¹⁴)(R¹⁵)—O-lower alkyl;

(c) lower alkyl;

(d) —CH₂OR⁸;

(e) CN;

(f) —CH₂CN;

(g) haloalkyl, preferably fluoroalkyl;

(h) —CON(R⁸)(R⁸);

(i) halo; or

(j) —OR⁸;

R⁸ is:

(a) hydrogen;

(b) K; or

(c) R⁹;

alternatively, R⁵ and R⁵′, R⁶ and R⁷ or R⁷ and R⁸ together with thecarbon to which they are attached form a saturated monocyclic ring of 3,4, 5, 6 or 7 atoms; optionally containing up to two heteroatoms selectedfrom oxygen, S(O)_(o) or NR_(i);

R⁹ is:

(a) lower alkyl;

(b) lower alkyl-CO₂D¹;

(c) lower alkyl-NHD¹;

(d) phenyl or mono-, di- or tri-substituted phenyl, wherein thesubstituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) lower alkyl-CO₂D¹;

(6) lower alkyl-NHD¹;

(7) CN;

(8) CO₂D¹; or

(9) haloalkyl, preferably fluoroalkyl;

(e) benzyl, mono-, di- or tri-substituted benzyl, wherein thesubstituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) lower alkyl-CO₂D¹;

(6) lower alkyl-NHD¹;

(7) CN;

(8) —CO₂D¹; or

(9) haloalkyl, preferably CF₃;

(f) cycloalkyl;

(g) K; or

(h) benzoyl, mono-, di-, or trisubstituted benzoyl, wherein thesubstituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) lower alkyl-CO₂D¹;

(6) lower alkyl-NHD¹;

(7) CN;

(8) —CO₂D¹; or

(9) haloalkyl, preferably CF₃;

R¹⁰ and R¹⁰′ are each independently:

(a) hydrogen; or

(b) R¹¹;

R¹¹ is:

(a) lower alkyl;

(b) cycloalkyl;

(c) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl,wherein the substituents are each independently:

(1) halo;

(2) alkoxy;

(3) alkylthio;

(4) CN;

(5) haloalkyl, preferably CF₃;

(6) lower alkyl;

(7) N₃;

(8) —CO₂D¹;

(9) —CO₂-lower alkyl;

(10) —C(R¹²)(R¹³)—OD¹;

(11) —C(R¹²)(R¹³)—O-lower alkyl;

(12) lower alkyl-CO₂D¹;

(13) lower alkyl-CO₂R¹²;

(14) benzyloxy;

(15) —O-(lower alkyl)-CO₂D¹;

(16) —O-(lower alkyl)-CO₂R¹²; or

(17) —O-(lower alkyl)-NR¹²R¹³;

(d) unsubstituted, mono-, di- or tri-substituted heteroaryl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or said heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally 1, 2, or 3additional N atoms, and wherein said substituents are eachindependently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF₃;

(7) N₃;

(8) —C(R¹²)(R¹³)—OD¹; or

(9) —C(R¹²)(R¹³)—O-lower alkyl;

(e) unsubstituted, mono- or di-substituted benzoheterocycle, wherein thebenzoheterocycle is a 5, 6, or 7-membered ring which contains 1 or 2heteroatoms independently selected from O, S, or N, and, optionally, acarbonyl group or a sulfonyl group, wherein said substituents are eachindependently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF₃;

(7) N₃;

(8) —C(R¹²)(R¹³)—OD¹; or

(9) —C(R¹²)(R¹³)—O-lower alkyl;

(f) unsubstituted, mono- or di-substituted benzocarbocycle, wherein thecarbocycle is a 5, 6, or 7-membered ring which optionally contains acarbonyl group, wherein said substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF₃;

(7) N₃;

(8) —C(R¹²)(R¹³)—OD¹; or

(9) —C(R¹²)(R¹³)—O-lower alkyl;

(g) hydrogen; or

(h) K

R¹² and R¹³ are each independently:

(a) hydrogen;

(b) lower alkyl; or

(c) aryl; or

R¹² and R¹³ together with the atom to which they are attached form asaturated monocyclic ring of 3, 4, 5, 6 or 7 atoms;

R¹⁴ and R¹⁵ are each independently:

(a) hydrogen; or

(b) lower alkyl; or

R¹⁴ and R¹⁵ together with the atom to which they are attached form acarbonyl, a thial, or a saturated monocyclic ring of 3, 4, 5, 6 or 7atoms;

D¹ is:

(a) hydrogen or

(b) D;

D is:

(a) V; or

(b) K;

U is:

(a) oxygen;

(b) sulfur; or

(c) —N(R_(a))(R_(I))—;

V is:

(a) —NO;

(b) —NO₂; or

(c) hydrogen

K is—W_(aa)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(j)—W_(g)—(C(R_(e))(R_(f)))_(z)—U—V;wherein aa, b, c, d, g, i and j are each independently an integer from 0to 3;

p, x, y and z are each independently an integer from 0 to 10;

W at each occurrence is independently:

(a) —C(O)—;

(b) —C(S)—;

(c) —T—;

(d) —(C(R_(e))(R_(f)))_(h)—;

(e) alkyl;

(f) aryl;

(g) heterocyclic ring;

(h) arylheterocyclic ring, or

(i) —(CH₂CH₂O)_(q)—;

E at each occurrence is independently:

(a) —T—;

(b) alkyl;

(c) aryl;

(d) —(C(R_(e))(R_(f)))_(h)—;

(e) heterocyclic ring;

(f) arylheterocyclic ring; or

(g) —(CH₂CH₂O)_(q)—;

h is an integer form 1 to 10;

q is an integer from 1 to 5;

R_(e) and R_(f) are each independently:

(a) hydrogen;

(b) alkyl;

(c) cycloalkoxy;

(d) halogen;

(e) hydroxy;

(f) hydroxyalkyl;

(g) alkoxyalkyl;

(h) arylheterocyclic ring;

(i) cycloalkylalkyl;

(j) heterocyclicalkyl;

(k) alkoxy;

(l) haloalkoxy;

(m) amino;

(n) alkylamino;

(o) dialkylamino;

(p) arylamino;

(q) diarylamino;

(r) alkylarylamino;

(s) alkoxyhaloalkyl;

(t) haloalkoxy;

(u) sulfonic acid;

(v) alkylsulfonic acid;

(w) arylsulfonic acid;

(x) arylalkoxy;

(y) alkylthio;

(z) arylthio;

(aa) cyano;

(bb) aminoalkyl;

(cc) aminoaryl;

(dd) alkoxy;

(ee) aryl;

(ff) arylalkyl;

(gg) carboxamido;

(hh) alkylcarboxamido;

(ii) arylcarboxamido;

(jj) amidyl;

(kk) carboxyl;

(ll) carbamoyl;

(mm) alkylcarboxylic acid;

(nn) arylcarboxylic acid;

(oo) alkylcarbonyl;

(pp) arylcarbonyl;

(qq) ester;

(rr) carboxylic ester;

(ss) alkylcarboxylic ester;

(tt) arylcarboxylic ester;

(uu) haloalkoxy;

(vv) sulfonamido;

(ww) alkylsulfonamido;

(xx) arylsulfonamido;

(yy) alkylsulfonyl,

(zz) alkylsulfonyloxy,

(aaa) arylsulfonyl,

(bbb) arylsulphonyloxy

(ccc) sulfonic ester;

(ddd) carbamoyl;

(eee) urea;

(fff) nitro; or

(ggg) —U—V; or

R_(e) and R_(f) taken together are:

(a) oxo;

(b) thial; or

R_(e) and R_(f) taken together with the carbon to which they areattached are:

(a) heterocyclic ring;

(b) cycloalkyl group; or

(c) bridged cycloalkyl group;

k is an integer from 1 to 2;

T at each occurrence is independently:

(a) a covalent bond,

(b) carbonyl,

(c) an oxygen,

(d) —S(O)_(o)—; or

(e) —N(R_(a))(R_(I))—;

o is an integer from 0 to 2;

Q is:

(a) —C(O)—U—D¹;

(b) —CO₂-lower alkyl;

(c) tetrazolyl-5-yl;

(d) —C(R⁷)(R⁸)(S—D¹);

(e) —C(R⁷)(R⁸)(O—D¹); or

(f) —C(R⁷)(R⁸)(O-lower alkyl);

R_(a) is:

(a) a lone pair of electron;

(b) hydrogen; or

(c) lower alkyl;

R_(i) is:

(a) hydrogen;

(b) alkyl;

(c) aryl;

(d) alkylcarboxylic acid;

(e) arylcarboxylic acid;

(f) alkylcarboxylic ester;

(g) arylcarboxylic ester;

(h) alkylcarboxamido;

(i) arylcarboxamido;

(j) alkylsulfinyl;

(k) alkylsulfonyl;

(l) alkylsulfonyloxy,

(m) arylsulfinyl;

(n) arylsulfonyl;

(o) arylsulphonyloxy;

(p) sulfonamido;

(q) carboxamido;

(r) carboxylic ester;

(s) aminoalkyl;

(t) aminoaryl;

(u) —CH—²C(U—V)(R_(e))(R_(f));

(v) a bond to an adjacent atom creating a double bond to that atom; or

(w) —(N₂O₂—)⁻.M⁺, wherein M⁺ is an organic or inorganic cation;

with the proviso that the compounds of Formula I must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

In cases where R_(e) and R_(f) are a heterocyclic ring or R_(e) andR_(f) taken together with the carbon atoms to which they are attachedare a heterocyclic ring, then R_(i) can be a substituent on anydisubstituted nitrogen contained within the radical where R_(i) is asdefined herein.

In cases where multiple designations of variables which reside insequence are chosen as a “covalent bond” or the integer chosen is 0, theintent is to denote a single covalent bond connecting one radical toanother. For example, E₀ would denote a covalent bond, while E₂ denotes(E—E) and (C(R_(e))(R_(f)))₂ denotes —C(R_(e))(R_(f))—C(R_(e))(R_(f))—.

Another embodiment of the present invention provides compounds of theFormula (II):

wherein:

A—B is:

(a) N—C;

(b) C—N; or

(c) N—N;

when sides d and f are double bonds, and sides e and g are single bonds,—X²—Y²—Z²— is:

(a) ═CR⁴—CR⁴′═CR⁵—;

(b) ═N—CR⁴═CR⁴′—,

(c) ═N—CR⁴═N—;

(d) ═CR⁴—N═CR⁴′—;

(e) ═CR⁴—N═N—;

(f) ═N—N═CR⁴—;

(g) ═N—N═N—;

(h) ═CR⁴—CR⁵═N—; or

(i) ═CR^(2′)—CR⁵═N—;

R² and R^(2′) taken together are:

or R^(2′) and R⁵ taken together with the carbon atoms to which they areattached are:

(a) cycloalkyl; or

(b) heterocyclic ring;

R⁹⁷ is:

(a) hydrogen;

(b) alkylthio;

(c) alkylsulfinyl;

(d) alkylsulfonyl;

(e) cyano;

(f) carboxyl;

(g) amino;

(h) lower alkyl;

(i) haloalkyl;

(j) hydroxy;

(k) alkoxy;

(l) haloalkoxy;

(m) alkylarylalkylamino;

(n) aminoalkyl;

(o) aminoaryl;

(p) sulfonamido;

(q) alkylsulfonamido;

(r) arylsulfonamido;

(s) heterocyclic ring;

(t) hydroxyalkyl; or

(u) nitro;

a is an integer from 1 to 3;

when sides e and g are double bonds, and sides d and f are single bonds,—X²—Y²—Z²— is:

(a) —CR⁴═N—N═;

(b) —N═N—CR⁴═;

(c) —CR⁴═N—CR⁴′—;

(d) —N═CR⁴—N═;

(e) —CR⁴═CR⁴′—N═;

(f) —N═CR⁴—CR⁵═;

(g) —CR⁴═CR⁵—CR^(5′)—; or

(h) —N═N—N═;

when side g is a double bond, and sides d, e and f are single bonds,—X²—Y²—Z²— is:

(a) —C(O)—O—CR⁴═;

(b) —C(O)—NR³—CR⁴═;

(c) —C(O)—S—CR⁴═; or

(d) —C(H)R⁴—C(OH)R⁵—N═;

when sides d is a double bond, and sides e, f and g are single bonds,—X²—Y²—Z²— is:

(a) ═CR⁴—O—C(O)—;

(b) ═CR⁴—NR³—C(O)—;

(c) ═CR⁴—S—C(O)—; or

(d) ═N—C(OH)R⁴—C(H)R⁵—;

when sides f is a double bond, and sides d, e and g are single bonds,—X²—Y²—Z²— is:

(a) —CH(R⁴)—CR⁵═N—; or

(b) —C(O)—CR⁴═CR⁵—;

when sides e is a double bond, and sides d, f and g are single bonds,—X²—Y²—Z²— is:

(a) —N═CR⁴—CH(R⁵)—; or

(b) —CR⁴═CR⁵—C(O)—;

when sides d, e, f and g are single bonds, —X²—Y²—Z²— is:

(a) —C(O)—CR⁴(R^(4′))—C(O)—;

R¹, R^(1′), R², R³, R⁴, R⁴′, R⁵ and R⁵′ are as defined herein;

with the proviso that the compounds of Formula II must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (III):

wherein:

X³ is:

(a) —C(O)—U—D¹;

(b) —CH₂—U—D¹;

(c) —CH₂—C(O)—CH₃;

(d) —CH₂—CH₂—C(O)—U—D¹;

(e) —CH₂—O—D¹; or

(f) —C(O)H

Y³ is:

(a) —(CR⁵(R⁵′))_(k)—U—D¹;

(b) —CH₃;

(c) —CH₂OC(O)R⁶; or

(d) —C(O)H;

alternatively, X³ and Y³ taken together are—CR⁸²(R⁸³)—CR^(82′))—(R^(83′))—;

R⁸², R^(82′), R⁸³ and R^(83′) are each independently:

(a) hydrogen;

(b) hydroxy;

(c) alkyl;

(d) alkoxy;

(e) lower alkyl-OD¹;

(f) alkylthio;

(g) CN;

(h) —C(O)R⁸⁴; or

(i) —OC(O)R⁸⁵;

R⁸⁴ is:

(a) hydrogen;

(b) lower alkyl; or

(c) alkoxy;

R⁸⁵ is:

(a) lower alkyl;

(b) alkoxy

(c) unsubstituted, mono-, di- or tri-substituted phenyl or pyridyl,wherein the substituents are each independently:

(1) halo;

(2) alkoxy;

(3) haloalkyl;

(4) CN;

(5) —C(O)R⁸⁴;

(6) lower alkyl;

(7) —S(O)_(o)-lower alkyl; or

(8) —OD¹;

alternatively, R⁸² and R⁸³ or R^(82′) and R^(83′) taken together are:

(a) oxo;

(b) thial;

(c) ═CR⁸⁶R⁸⁷; or

(d) ═NR⁸⁸;

R⁸⁶ and R⁸⁷ are each independently:

(a) hydrogen;

(b) lower alkyl;

(c) lower alkyl-OD¹;

(d) CN; or

(e) —C(O)R⁸⁴;

R⁸⁸ is:

(a) OD¹;

(b) alkoxy;

(c) lower alkyl; or

(d) unsubstituted, mono-, di- or tri-substituted phenyl or pyridyl,wherein the substituents are each independently:

(1) halo;

(2) alkoxy;

(3) haloalkyl;

(4) CN;

(5) —C(O)R⁸⁴;

(6) lower alkyl;

(7) —S(O)_(o)-lower alkyl; or

(8) —OD¹;

R¹, R², R⁵, R⁵′, R⁶, U, D¹, o and k are as defined herein;

with the proviso that the compounds of Formula III must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (IV)

wherein:

X⁴ and Z⁴ are each independently:

(a) N; or

(b) CR²¹;

R²⁰ is:

(a) —S(O)₂—CH;

(b) —S(O)₂—NR⁸(D¹); or

(c) —S(O)₂—N(D¹)—C(O)—CF₃;

R²¹ and R^(21′) are each independently:

(a) hydrogen;

(b) lower alkyl;

(c) alkoxy;

(d) alkylthio;

(e) haloalkyl, preferably fluoroalkyl;

(f) haloalkoxy, preferably fluoroalkoxy;

(g) CN;

(h) —CO₂D¹;

(i)—CO₂R¹⁴;

(j) lower alkyl-O—D¹;

(k) lower alkyl-CO₂D¹;

(l) lower alkyl-CO₂R¹⁴;

(m) halo;

(n) —O—D¹;

(o) —N₃;

(p) —NO₂;

(q) —NR¹⁴D¹;

(r) —N(D¹)C(O)R¹⁴;

(s) —NHK;

(t) aryl;

(u) arylalkylthio;

(v) arylalkoxy;

(w) alkylamino;

(x) aryloxy;

(y) alkylarylalkylamino;

(z) cycloalkylalkylamino; or

(aa) cycloalkylalkoxy;

R²² is:

(a) mono-, di- or tri-substituted phenyl or pyridinyl (or the N-oxidethereof), wherein the substituent are each independently:

(1) hydrogen;

(2) halo;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) lower alkyl;

(7) haloalkyl, preferably fluoroalkyl;

(8) N₃;

(9) —CO₂D¹;

(10) —CO₂-lower alkyl;

(11) —C(R¹⁴)(R¹⁵)—OD¹;

(12) —OD¹;

(13) lower alkyl-CO₂—R¹⁴; or

(14) lower alkyl-CO₂—D¹;

(b) —T—C(R²³)(R²⁴)—(C(R²⁵)(R²⁶))_(o)—C(R²⁷)(R²⁸)—U—D¹;

(d) arylalkyl; or

(e) cycloalkylalkyl;

wherein:

R¹⁴ and R¹⁵ are each independently:

(a) hydrogen; or

(b) lower alkyl;

R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸ are each independently:

(a) hydrogen; or

(b) lower alkyl; or

R²³ and R²⁷, or R²⁷ and R²⁸ together with the atoms to which they areattached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R²³ andR²⁵ are joined to form a covalent bond;

Y⁵ is:

(a) CR²⁹R³⁰;

(b) oxygen; or

(c) sulfur;

R²⁹ and R³⁰ are each independently:

(a) hydrogen;

(b) lower alkyl;

(c) (CH₂)_(o)—OD¹;

(d) halo; or

R²⁹ and R³⁰ taken together are an oxo group;

s is an integer from 2 to 4;

R⁸, D¹, T, U, K and o are as defined herein;

with the proviso that the compounds of Formula IV must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (V):

wherein:

X⁵ is:

(a) oxygen; or

(b) sulfur;

R³¹ is:

(a) alkoxy;

(b) haloalkoxy preferably —OCH₂F, —OCHF₂, or —OCHF₂;

(c) alkylthio;

(d) haloalkyl, preferably CF₃;

(e) halo; or

(f) lower alkyl;

R³², R³³, R³⁴, R³⁵, R³⁶ and R³⁷ are each independently:

(a) hydrogen;

(b) halo, preferably F or Cl;

(c) lower alkyl;

(d) cycloalkyl;

(e) haloalkyl, preferably CF₃, CF₂H or CFH₂;

(f) —OD¹;

(g) —OR⁴³;

(h) —SD¹;

(i) —SR⁴³;

(j) —S(O)R⁴³;

(k) —S(O)₂R⁴³;

(l) unsubstituted, mono- or di-substituted benzyl, wherein thesubstituents are each independently:

(1) haloalkyl, preferably CF₃;

(2) CN;

(3) halo;

(4) lower alkyl;

(5) —OR⁴³;

(6) —SR⁴³;

(7) —S(O)R⁴³; or

(8) —S(O)₂R⁴¹;

(m) phenyl or mono- or di-substituted phenyl, wherein the substituentsare each independently:

(1) haloalkyl, preferably CF₃;

(2) CN;

(3) halo;

(4) lower alkyl;

(5) —OR⁴³;

(6) —SR⁴³;

(7) —S(O)R⁴³; or

(8) —S(O)₂R⁴¹; or

R³² together with R³³ form an oxo group; or

R³⁴ together with R³⁵ form an oxo group; or

R³⁶ together with R³⁷ form an oxo group; or

R³² and R³³ are joined so that, together with the carbon atom to whichthey are attached, they form a saturated monocyclic ring of 3, 4, 5, 6or 7 members, and, optionally, contain one heteroatom which ispreferably oxygen; or

R³³ and R³⁴ are joined so that, together with the carbon atoms to whichthey are attached, they form a saturated or aromatic monocyclic ring of3, 4, 5, 6 or 7 members; or

R³³ and R³⁶ are joined so that, together with the carbon atoms to whichthey are attached, they form a saturated or aromatic monocyclic ring of3, 4, 5, 6 or 7 members; or

R³⁴ and R³⁵ are joined so that, together with the carbon atom to whichthey are attached, they form a saturated monocyclic ring of 3, 4, 5, 6or 7 members, and optionally, contain one heteroatom which is preferablyoxygen; or

R³⁴ and R³⁶ are joined so that, together with the carbon atoms to whichthey are attached, they form a saturated or aromatic monocyclic ring of3, 4, 5, 6 or 7 members; or

R³⁶ and R³⁷ are joined so that, together with the carbon atom to whichthey are attached, they form a saturated monocyclic ring of 3,4,5,6 or 7members, and, optionally, contain one heteroatom which is preferablyoxygen;

R³⁸ and R³⁹ are hydrogen or R³⁸ and R³⁹ when taken together are oxo;

R⁴⁰, R⁴¹ and R⁴² are each independently:

(a) hydrogen;

(b) halo;

(c) lower alkyl;

(d) alkoxy;

(e) alkylthio;

(f) —S(O)-lower alkyl;

(g) haloalkyl, preferably CF₃;

(h) CN;

(i) —N₃;

(j) —NO₂;

(k) —SCF₃; or

(l) —OCF₃;

R⁴³ is:

(a) lower alkyl; or

(b) benzyl, optionally mono- or di-substituted, wherein the substituentsare each independently:

(1) haloalkyl, preferably CF₃;

(2) CN;

(3) halo; or

(4) lower alkyl;

alternatively, X⁵ and U taken together with the carbon atom to whichthey are attached form a 5-, 6-, or 7-membered heterocyclic ring;

n at each occurrence is an integer from 0 to 1; and

D¹, U and K are as defined herein;

with the proviso that the compounds of Formula V must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (VI):

wherein:

X⁶ is:

(a) oxygen;

(b) sulfur;

(c) CH₂;

(d) —S(O)_(o);

(e) —NH; or

(f) —C(O);

Z⁶ is:

(a) K;

(b) —C(O)CH₃; or

(c) hydrogen;

R⁴⁵ is:

(a) lower alkyl; or

(b) mono-, di-, tri-, tetra- or per-substituted lower alkyl, wherein thesubstituent is halo, preferably fluoro;

R⁴⁶ is:

(a) mono or disubstituted aromatic ring of 5 atoms containing one O, Sor N atom, and, optionally, 1, 2 or 3 additional N atoms, wherein thesubstituents are each independently:

(1) hydrogen;

(2) lower alkyl;

(3) halo;

(4) —O-lower alkyl;

(5) —S-lower alkyl;

(6) haloalkyl, preferably CF₃;

(7) —COCH₃; or

(8) —S(O)₂-lower alkyl;

(b) mono or disubstituted aromatic ring of 6 atoms containing 0, 1, 2, 3or 4 nitrogen atoms, wherein the substituents are each independently:

(1) hydrogen;

(2) lower alkyl;

(3) halo;

(4) —O-lower alkyl;

(5) —S-lower alkyl;

(4) —O-haloalkyl;

(5) —S-haloalkyl;

(6) haloalkyl, preferably CF₃;

(7) CN;

(8) —N₃;

(9) —COCH₃;

(10) —S(O)₂-lower alkyl;

(11) alkenyl; or

(12) alkynyl;

(c) cycloalkylalkyl;

(d) unsubstituted, mono-, di-, tri-, or tetra substituted phenyl ornaphthyl, wherein the substituents are each independently:

(1) halo;

(2) CN;

(3) haloalkyl, preferably CF₃;

(4) —N₃;

(5) vinyl;

(6) acetylenyl;

(7) lower alkyl;

(8) alkoxy;

(9) haloalkoxy;

(10) alkylthio; or

(11) haloalkylthio;

(e) unsubstituted, mono-, di-, tri-, or tetra substitutedbenzoheteroaryl, wherein the substituents are each independently:

(1) halo;

(2) CN; or

(3) haloalkyl, preferably CF₃;

(f) substituted lower alkyl;

(g) substituted alkenyl;

(h) cycloalkyl; or

(i) lower alkyl-O-lower alkyl;

R⁴⁷ is:

(a) —C(O)-lower alkyl;

(b) —CN;

(c) —CO₂D¹;

(d) —CO₂-lower alkyl ester;

(e) —C(O)—NHD¹;

(f) —S(O)-lower alkyl;

(g) —S(O)₂-lower alkyl;

(h) —NO₂;

(i) haloalkyl, preferably CF₃;

(j) halo;

(k) K;

(l) —S(O)_(o)NR¹⁰R¹¹; or

(m)—S(O)_(o)NR¹²R¹³;

R ⁴⁸ is:

(a) hydrogen; or

(b) lower alkyl; or

R⁴⁷ and R⁴⁸ taken together with the atoms to which they are attachedform a 5, 6, or 7-membered unsubstituted, mono-, di-, or trisubstitutedsaturated or unsaturated cyclic ring optionally containing a—S(O)₂-group, wherein the substituents are each independently:

(a) oxo;

(b) lower alkyl;

(c) OD¹; or

(d) ═N—OD¹;

R¹⁰, R¹¹, R¹², R¹³, K, D¹ and o are as defined herein;

with the proviso that the compounds of Formula VI must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds ofFormula (VII):

wherein:

X⁷ is:

(a) oxygen;

(b) sulfur;

(c) —NR⁵¹;

(d) —N—O—R⁵²; or

(e) —N—NR⁵²R⁵³;

Y⁷ is:

(a) hydrogen;

(b) halo;

(c) lower alkyl;

(d) alkenyl; or

(e) alkynyl;

Z⁷ is:

(a) —C(O)—;

(b) oxygen;

(c) —S(O)_(o)—;

(d) —NR⁹³—; or

(e) covalent bond;

R⁴⁹ is:

(a) R³; or

(b) R⁴ ;

R⁵⁰ and R⁵⁰′ are each independently:

(a) hydrogen;

(b) halo;

(c) lower alkyl;

(d) aryl;

(e) arylalkyl;

(f) cycloalkyl;

(g) cycloalkylalkyl;

(h) —OD¹;

(i) lower alkyl-OD¹;

(j) carboxamido;

(k) amidyl; or

(l) K;

R⁵¹ is:

(a) lower alkyl;

(b) alkenyl;

(c) cycloalkyl;

(d) cycloalkylalkyl;

(e) aryl;

(f) arylalkyl;

(g) heterocyclic ring; or

(h) lower alkyl-heterocyclic ring;

R⁵² and R⁵³ are each independently:

(a) lower alkyl;

(b) cycloalkyl;

(c) cycloalkylalkyl;

(d) aryl;

(e) arylalkyl;

(f) heterocyclic ring; or

(g) heterocyclicalkyl;

R⁹³ is:

(a) hydrogen; or

(b) lower alkyl;

R¹, R³, R⁴, K, D¹ and o are as defined herein;

with the proviso that the compounds of Formula VII must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (VIII):

wherein:

X⁸ is:

(a) oxygen;

(b) sulfur;

(c) NR_(i); or

(d) —CR⁵⁸R⁵⁹;

A¹, A², A³, and A⁴ are each independently carbon or nitrogen, with theproviso that at least two of A¹, A², A³, and A⁴ are carbon atoms;

R⁵⁴ is:

(a) haloalkylalkyl, preferably fluoroalkylalkyl;

(b) halo;

(c) alkylthio;

(d) alkoxy;

(e) —NO₂;

(f) CN;

(g) lower alkyl-CN;

(h) heterocyclic ring;

(i) lower alkyl;

(j) arylalkyl;

(k) cycloalkyl; or

(l) phenyl or mono- or di-substituted phenyl, wherein the substituentsare each independently:

(1) alkylthio;

(2) nitro; or

(3) alkylsulfonyl;

R⁵⁵ is:

(a) —CO₂D¹;

(b) —C(O)—N(R⁸)(R⁸);

(c) —CO₂-lower alkyl;

(d) —C(O)—N(D¹)—S(O)₂—(C(R_(e))(R_(f)))_(p)—U—V; or

(e) —CO₂-lower alkyl-U—V;

R⁵⁶ is:

(a) hydrogen;

(b) phenyl;

(c) thienyl;

(d) alkynyl;

(e) alkenyl; or

(f) alkyl;

R_(g) is:

(a) hydrogen;

(b) lower alkyl;

(c) arylalkyl;

(d) alkoxy;

(e) aryloxy;

(f) arylalkoxy;

(g) haloalkyl;

(h) haloalkoxy;

(i) alkylamino;

(j) arylamino;

(k) arylalkylamino;

(l) nitro;

(m) sulfonamido;

(n) carboxamido;

(o) aryl;

(p) —C(O)-aryl; or

(q) —C(O)-alkyl;

alternatively, R_(g) and the monocyclic ring radical of which A¹, A²,A³, and A⁴ comprise four of the six atoms are:

(a) naphthyl;

(b) quinolyl;

(c) isoquinolyl;

(d) quinolizinyl;

(e) quinoxalinyl; or

(f) dibenzofuryl;

R⁵⁸ and R⁵⁹ are each independently:

(a) hydrogen;

(b) lower alkyl;

(c) lower alkyl-phenyl;

(d) haloalkyl, preferably fluoroalkyl;

(e) halo;

(f) —NO₂;

(g) CN;

(h) lower alkyl-CN;

(i) alkoxy;

(j) alkylthio; or

(k) alkenyl;

alternatively, R⁵⁸ and R⁵⁹ taken together along with the atoms to whichthey are attached are cycloalkyl;

R⁸, R_(i), R_(e), R_(f), D¹, U, V, a and p are as defined herein;

with the proviso that the compounds of Formula VIII must contain atleast one nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (IX):

wherein:

X⁹ is —C(O)—U—D¹and Y⁹ is —CH₂—CR⁵(R⁵′)—U—D^(1;); or

X⁹ is —CH₂—CR⁵(R⁵′)—U—D¹ and Y⁹ is —C(O)—U—D¹; or

X⁹ and Y⁹ taken together are:

(a) —C(O)—O—CR⁴(R^(4′))—CR⁵(R^(5′))—;

(b) —(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—CR⁵(R^(5′))—;

(c) —C(O)—(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—;

(d) —(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—C(O)—; or

(e) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

wherein X⁹ is the first carbon atom of a, b, c, d and e;

R¹, R², R⁴, R⁴′, R⁵, R⁵′, U, D¹ and k are as defined herein;

with the proviso that the compounds of Formula IX contain at least onenitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (X):

wherein:

when side h, k, and j are single bonds, and side i and l are a doublebond, —X¹⁰—Y¹⁰—Z¹⁰— is:

when sides i, k and l are single bonds, and sides h and j are doublebonds, —X¹⁰—Y¹⁰—Z¹⁰— is:

when side h and j are single bonds, and side k and i is a single or adouble bond, —X¹⁰—Y¹⁰—Z¹⁰— is:

P¹⁰ is:

(a) —N═;

(b) —NR³—;

(c) —O—; or

(d) —S—;

Q¹⁰ and Q^(10′) are each independently:

(a) CR⁶⁰; or

(b) nitrogen;

A¹⁰B¹⁰—C¹⁰D¹⁰— is:

(a) —CR⁴═CR^(4′)—CR⁵═CR ^(5′)—;

(b) —CR⁴(R^(4′))—CR⁵(R^(5′))—CR⁴(R_(4′))—C(O)—;

(c) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—CR⁴(R^(4′))—;

(d) —CR⁴(R^(4′))—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

(e) —C(O)—CR⁴(R^(4′))—C R⁵(R^(5′))—CR⁴(R^(4′))—;

(f) —CR⁴(R^(4′))—CR⁵(R_(5′))—C(O)—;

(g) —CR⁴(R^(4′))—C(O)—CR⁵(R^(5′))—;

(h) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

(i) —CR⁴(R^(4′))—CR⁵(R^(5′))—O—C(O)—;

(j) —CR⁴(R^(4′))—O—C(O)—CR⁵(R^(5′))—;

(k) —O—C(O)—CR⁴(R^(4′))—CR⁵(R_(5′))—;

(l) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—O—;

(m) —CR⁴(R^(4′))—C(O)—O—CR⁵(R^(5′))—;

(n) —C(O)—O—CR⁴(R^(4′))—CR⁵(R^(5′))—;

(o) —CR¹²(R¹³)—O—C(O)—;

(p) —C(O)—O—CR¹²(R¹³)—;

(q) —O—C(O)—CR¹²(R¹³)—;

(r) —CR¹²(R¹³)—C(O)—O—;

(s) —N═CR⁴—CR^(4′)═CR⁵—;

(t) —CR⁴═N—CR^(4′)═CR⁵—;

(u) —CR⁴═CR^(4′)—N═CR⁵—;

(v) —CR⁴═CR⁵—CR^(5′)═N—;

(w) —N═CR⁴—CR^(4′)═N—;

(x) —N═CR⁴—N═CR^(4′)—;

(y) —CR⁴═N—CR^(4′)═N—;

(z) —S—CR⁴═N—;

(aa) —S—N═CR⁴—;

(bb) —N═N—NR³—

(cc) —CR⁴═N—S—;

(dd) —N═CR⁴—S—;

(ee) —O—CR⁴═N—;

(ff) —O—N═CR⁴—; or

(gg) —N═CR⁴—O—;

—A^(10′)B^(10′)D^(10′) is:

(a) —CR⁴═CR⁵—CR^(5′)═

(b) —CR⁴(R^(4′))—CR⁵(R^(5′))—CR⁴(R^(4′))—;

(c) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

(d) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—;

(e) —N═CR⁴—CR⁵═;

(g) —N═N—CR⁴═;

(h) —N═N—NR³—;

(i) —N═N—N═;

(j) —N═CR⁴—NR³—;

(k) —N═CR⁴—N═;

(l) —CR⁴═N—NR³;

(m) —CR⁴═N—N═;

(n) —CR⁴═N—CR⁵═;

(o) —CR⁴═CR⁵—NR³—;

(p) —CR⁴═CR⁵—N═;

(q) —S—CR⁴═CR⁵—;

(r) —O—CR⁴═CR⁵;

(s) —CR⁴═CR⁵—;

(t) —CR⁴═CR⁵—S—;

(u) —CR⁴═N—S—;

(v) —CR⁴═N—O—;

(w) —N═CR⁴—S—;

(x) —N═CR⁴—O—;

(y) —S—CR⁴═N—;

(z) —O—CR⁴═N—;

(aa) —N═N—S—;

(bb) —N═N—O—,

(cc) —S—N═N—,

(dd) —O—N═N—;

(ee) —CR⁴═CR⁵—S;

(ff) —CR⁴(R^(4′))—CR⁵(R^(5′))—S—;

(gg) —CR⁴(R^(4′))—CR⁵(R^(5′))—O—;

(hh) —S—CR⁴(R^(4′))—CR⁵(R^(5′))—; or

(ii) —O—CR⁴(R^(4′))—CR⁵(R^(5′))—;

R⁶⁰ and R⁶¹ are each independently:

(a) lower alkyl;

(b) haloalkyl, preferably fluoroalkyl;

(c) alkoxy;

(d) alkylthio;

(e) lower alkyl-OD¹;

(f) —C(O)H;

(h) —(CH₂)_(q)—CO₂-lower alkyl;

(i) —(CH₂)_(q)—CO₂D¹;

(j) —O—(CH₂)_(q)—S-lower alkyl;

(k) —(CH₂)_(q)—S-lower alkyl;

(l) —S(O)₂-lower alkyl;

(m) —(CH₂)_(q)—NR¹²R¹³; or

(n) —C(O)N(R⁸)(R⁸);

R₁, R², R³, R⁴, R^(4′), R⁵, R^(5′), R⁸, R¹², R¹³, T, D¹ and q are asdefined herein;

with the proviso that the compounds of Formula X must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (XI):

wherein:

X¹¹ is:

(a) oxygen; or

(b) CH₂;

Y¹¹ is:

(a) oxygen;

(b) —H₂;

(c) —N—OD¹;

(d) —N—O-lower alkyl;

(e) —N—O-aryl;

(f) —N—C(O)—O-lower alkyl;

(g) —N—N(R⁸)(R⁸); or

(h) —N—N(R₈)—S(O)₂-lower alkyl;

R⁶², R₆₃, R⁶⁴ and R⁶⁵ are each independently:

(a) hydrogen;

(b) lower alkyl;

(c) alkoxy;

(d) halo;

(e) CN;

(f) OD¹;

(g) aryloxy;

(h) —NR¹²R¹³;

(i) —CF₃;

(j) —NO₂;

(k) alkylthio;

(l) —S(O)_(o)-lower alkyl;

(m) —C(O)N(R⁸)(R⁸);

(n) —CO₂D¹

(o) —CO₂-lower alkyl; or

(p) —NR⁸—C(O)-lower alkyl;

R⁶⁶ is:

(a) hydrogen;

(b) lower alkyl;

(c) alkenyl;

(d) alkoxyalkyl; or

(e) cycloalkylalkyl;

R⁸, R¹², R¹³, o, K and D¹ are as defined herein;

with the proviso that the compounds of Formula XI must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (XII):

wherein:

X¹² is:

(e) —NR⁷³(R⁷⁴);

(f) hydrogen; or

(g) K;

Z¹² is:

(b) R⁶⁷;

R⁶⁷ is:

(a) hydrogen;

(b) lower alkyl;

(c) lower alkyl-OD¹;

(d) —OD¹;

(e) haloalkyl; or

R⁶⁸ is:

(a) lower alkyl;

(c) alkoxy

(d) mono-, di-, tri, tetra- or penta-substituted phenyl, wherein thesubstituent are each independently:

(1) hydrogen;

(2) halo;

(3) alkoxy;

(4) alkylthio;

(5) —S(O)_(o)-lower alkyl;

(6) lower alkyl;

(7) haloalkyl;

(8) —CO₂D¹;

(9) -lower alkyl-CO₂D¹;

(10) —OD¹;

(11) -lower alkyl-OD¹; or

(12) haloalkoxy;

(e) mono-, di-, or tri-substituted heteroaryl, wherein the heteroaryl isa monocyclic aromatic ring of 5 atoms, said ring having one heteroatomwhich is S, O, or N, and, optionally, 1, 2, or 3 additional N atoms; orthe heteroaryl is a monocyclic ring of 6 atoms, said ring having oneheteroatom which is N, and, optionally, 1,2,3, or 4 additional N atoms;wherein the substituents are each independently:

(1) hydrogen;

(2) halo;

(3) lower alkyl;

(4) alkoxy;

(5) alkylthio;

(6) aryloxy;

(7) arylthio;

(8) —CO₂D¹;

(9) —C(O)NH(D¹)

(10) haloalkyl; or

(11) —OD¹;

(b) halo;

(c) alkoxy

(d) haloalkyl;

(e) alkylthio;

(f) haloalkylthio;

(g) —OCH₂—

(h) unsubstituted, mono-, or di-substituted heteroaryl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or said heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally 1, 2, or 3additional N atoms, and wherein said substituents are eachindependently:

(1) halo; or

(2) lower alkyl

(i) —S(O)_(o)-lower alkyl;

(j) —S(O)_(o)-lower haloalkyl;

(k) amino;

(l) alkylamino;

(m) dialkylamino;

(n) —N(H)SO₂-lower alkyl;

(o) N(H)SO₂-lower haloalkyl;

(p) nitro;

(q) cyano;

(r) —CO₂D¹;

(s) carboxylic ester;

(t) lower alkyl-OD¹;

(q) carboxamide; or

(r) —C(O)N(R¹²)D¹;

R⁶⁹ is:

(a) lower alkyl;

(b) hydrogen;

R⁷⁰ is:

(a) lower alkyl;

(b) hydrogen; or

(c) mono- or di-substituted phenyl, wherein the substituent are eachindependently:

(1) hydrogen;

(2) halo;

(3) alkoxy;

(4) haloalkyl; or

(5) lower alkyl;

R⁷¹ is:

(a) benzoyl, or mono-, or disubstituted benzoyl, wherein thesubstituents are each independently:

(1) halo;

(2) lower alkyl; or

(3) alkoxy;

(b) benzyl, mono- or disubstituted benzyl, wherein the substituents areeach independently:

(1) halo;

(2) lower alkyl; or

(3) alkoxy;

(c) lower alkyl-pyridinyl, or unsubstituted, mono-, or disubstitutedpyridinyl, wherein the substituents are each independently:

(1) halo;

(2) lower alkyl; or

(3) alkoxy;

(d) —C(O)-pyridinyl, or mono-, or disubstituted —C(O)-pyridinyl whereinthe substituents are each independently:

(1) halo;

(2) lower alkyl; or

(3) alkoxy;

(e) hydrogen;

(f) aryl;

(g) cycloalkyl;

(h) cycloalkylalkyl;

R⁷² is:

(a) lower alkenyl-CO₂D¹; or

(b) K;

R⁷³ is unsubstituted or mono substituted lower alkyl, wherein thesubstituents are each independently:

(a) hydroxy;

(b) alkoxy;

(c) nitro;

(c) —NH₂;

(d) alkylamino;

(e) dialkylamino;

(f) carboxyl;

(g) carboxylic ester; or

(h) carboxamide;

R⁷⁴ is:

(a) hydrogen;

(b) lower alkyl; or

(c) —C(O)R⁷⁶;

R⁷⁵ is:

(a) lower alkyl;

(b) haloalkyl

(c) substituted lower alkyl;

(d) cycloalkyl;

(e) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl,wherein the substituents are each independently:

(1) halo;

(2) alkoxy;

(3) —S(O)_(o)-lower alkyl;

(4) hydroxy;

(5) —S(O)_(o)-haloalkyl;

(6) lower alkyl;

(7) haloalkyl;

(8) —CO₂D¹;

(9) —CO₂-lower alkyl;

(10) —S(O)₂NR⁸(D¹);

(11) -lower alkyl-O-lower alkyl;

(12) —CN;

(13) lower alkyl-OD¹;

(14) arylalkoxy;

(15) —C(O)NR⁸(D¹); or

(16) aryl;

(f) mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl isa monocyclic aromatic ring of 5 atoms, said ring having one heteroatomwhich is selected from S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or4 additional N atoms; wherein the substituents are each independently:

(1) halo;

(2) alkoxy;

(3) —S(O)_(o)-lower alkyl;

(4) hydroxy;

(5) —S(O)_(o)-haloalkyl;

(6) lower alkyl;

(7) haloalkyl;

(8) —CO₂D¹;

(9) —CO₂-lower alkyl;

(10) —S(O)₂NR⁸(D¹);

(11) -lower alkyl-O-lower alkyl;

(12) —N(D¹)S(O)₂-lower alkyl;

(13) lower alkyl-OD¹;

(14) —N(D¹)S(O)₂-haloalkyl;

(15) —C(O)NR⁸(D¹); or

(16) aryl;

R⁷⁶ is:

(a) alkyl;

(b) substituted alkyl;

(c) alkyl-N(D¹)S(O)₂-aryl;

(d) substituted alkyl-cycloalkyl;

(e) substituted alkyl-heterocyclic ring; or

(f) arylalkoxy;

R⁷⁷ is:

(a) —OD¹;

(b) alkoxy; or

(c) —NR⁷⁸R⁷⁹;

R⁷⁸ and R⁷⁹ are each independently:

(a) hydrogen;

(b) hydroxy;

(c) alkoxy;

(d) lower alkyl; or

(e) substituted lower alkyl; or

R⁷⁸ and R⁷⁹ taken together with the nitrogen to which they are attachedform a heterocyclic ring;

R⁸⁰ and R⁸¹ are each independently:

(a) hydrogen;

(b) lower alkyl; or

(c) halo;

R⁸⁹ and R^(89′) are each independently:

(a) hydrogen; or

(b) lower alkyl; or

R⁸⁹ and R^(89′) taken together with the carbon to which they areattached form a cycloalkyl ring;

m is an integer from 0 to 6;

D¹, R¹, R⁸, R¹², K, X⁵, a, p and o are as defined herein; and

with the proviso that the compounds of Formula XII must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (XIII):

wherein:

X¹³ and Y¹³ are each independently:

(a) ═C(H)—; or

(b) ═N—;

R⁹⁰ is:

(a) lower alkyl;

(b) lower alkyl-OD¹;

(c) alkenyl;

(d) lower alkyl-CN;

(e) lower alkyl-CO₂D¹;

(f) aryl;

(g) heterocyclic ring; or

(i) heterocyclicalkyl;

R⁹¹ is:

(a) mono-, di- or tri-substituted phenyl, wherein the substituents areeach independently:

(1) hydrogen;

(2) halo;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl;

(7) lower alkyl;

(8) —CO₂D¹;

(9) —CO₂-lower alkyl;

(10) lower alkyl-OD¹;

(11) lower alkyl-NR¹²R¹³;

(12) lower alkyl-CO₂D¹; or

(13) —OD¹;

(b) mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl isa monocyclic aromatic ring of 5 atoms, said ring having one heteroatomwhich is S, O, or N, and, optionally, 1, 2, or 3 additional N atoms; orthe heteroaryl is a monocyclic ring of 6 atoms, said ring having oneheteroatom which is N, and, optionally, 1, 2, 3, or 4 additional Natoms; wherein the substituents are each independently:

(1) hydrogen;

(2) halo;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl;

(7) lower alkyl;

(8) —CO₂D¹;

(9) —CO₂-lower alkyl;

(10) lower alkyl-OD¹;

(11) lower alkyl-NR¹²R¹³;

(12) lower alkyl-CO₂D¹; or

(13) —OD¹;

D¹, R¹, R¹², and R¹³, are as defined herein; and

with the proviso that the compounds of Formula XIII must contain atleast one nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (XIV):

wherein:

X¹⁴ is:

(a) —C(O)—; or

(b) —C(S)—;

Y¹⁴ is:

(a) —O—; or

(b) —S—;

A¹⁴B¹⁴D¹⁴ is:

(a) —CR⁴═CR^(4′)—CR⁵═CR^(5′)—,

(b) —CR⁴(R_(4′))—CR⁵(R^(5′))—C)(O)—;

(c) —CR⁴(R^(4′))—C(O)—CR⁵(R^(5′))—;

(d) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

(e) —CR⁴(R⁵)—O—C(O)—;

(f) —C(O)—O—CR⁴(R⁵)—;

(g) —O—C(O)—CR⁴(R⁵)—;

(h) —S—N═CR⁴—;

(i) —O—N═CR⁴—;

(j) —CR⁴(R⁵)—NR³—C(O)—;

(k) —C(O)—NR³—CR⁴(R⁵)—;

(l) —NR³—C(O)—CR⁴(R⁵)—;

(m) —CR⁴(R⁵)—S—C(O)—;

(n) —C(O)—S—CR⁴(R⁵)—;

(o) —S—C(O)—CR⁴(R⁵)—;

(p) —CR⁴═CR^(4′)—C(O)—;

(q) —C(O)—CR⁴═CR^(4′)—;

(r) —O—CR⁴═CR^(4′)—;

(s) —S—CR⁴═CR^(4′)—;

(t) —NR³—CR⁴═CR⁵—;

(u) —S—NR³—C(O)—;

(v) —O—NR³—C(O)—; or

(w) —NR³—N═CR⁴—;

R¹, R², R³, R⁴, R^(4′), R⁵ and R^(5′) are as defined herein; and

with the proviso that the compounds of Formula XIV must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (XV):

wherein:

X¹⁵ is:

(a) —C(O)—;

(b) —CH₂—;

(c) —CH(OD¹)—;

(d) —C═N—O-lower alkyl-;

(e) —O—;

(f) —S(O)_(o)—;

(g) —NR⁹²; or

(g) covalent bond;

Y¹⁵ is:

(a) aryl; or

(b) cycloalkyl;

Z¹⁵ is:

(a) hydrogen;

(b) alkyl;

(c) haloalkyl;

(d) cycloalkyl;

(e) alkoxy;

(f) alkylthio;

(g) cycloalkylalkylthio;

(h) cycloalkylalkoxy;

(i) —OD¹;

(j) halo;

(k) cyano;

(l) —C(O)OD¹;

(m) —C(O)-lower alkyl;

R⁹² is:

(a) hydrogen;

(b) lower alkyl;

(c) —C(O)-lower alkyl; or

(d) K;

R¹, D¹, K and o are as defined herein; and

with the proviso that the compounds of Formula XV contain at least onenitrite, nitrate, thionitrite or thionitrate group.

Another embodiment of the present invention provides compounds of theFormula (XVI):

Y¹⁶ is:

(a) hydrogen;

(b) halogen;

(c) methyl; or

(d) ethyl;

Z¹⁶ is:

(a) hydrogen; or

(b) methyl;

R⁹³ is:

(a) chloro; or

(b) fluoro;

R⁹⁴ and R^(94′) are each independently:

(a) hydrogen; or

(b) fluoro;

R⁹⁵ is:

(a) chloro;

(b) fluoro;

(c) hydrogen;

(d) methyl;

(e) ethyl;

(f) methoxy;

(g) ethoxy; or

(i) hydroxy;

R⁹⁶ is:

(a) chloro;

(b) fluoro;

(c) trifluoromethyl; or

(d) methyl;

R⁹⁸ is:

(a) lower alkyl;

(b) lower alkenyl;

(c) alkoxy; or

(d) alkylthio;

K and X¹³ are as defined herein; and

with the proviso that the compounds of Formula XVI must contain at leastone nitrite, nitrate, thionitrite or thionitrate group.

Compounds of the present invention that have one or more asymmetriccarbon atoms may exist as the optically pure enantiomers, purediastereomers, mixtures of enantiomers, mixtures of diastereomers,racemic mixtures of enantiomers, diastereomeric racemates or mixtures ofdiastereomeric racemates. The present invention includes within itsscope all such isomers and mixtures thereof.

Another aspect of the present invention provides processes for makingthe novel compounds of the invention and to the intermediates useful insuch processes. The reactions are performed in solvents appropriate tothe reagents and materials used are suitable for the transformationsbeing effected. It is understood by one skilled in the art of organicsynthesis that the functionality present in the molecule must beconsistent with the chemical transformation proposed. This will, onoccasion, necessitate judgment by the routineer as to the order ofsynthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to one skilled in the art.The use of sulfur and oxygen protecting groups is well known forprotecting thiol and alcohol groups against undesirable reactions duringa synthetic procedure and many such protecting groups are known anddescribed by, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999).

The chemical reactions described herein are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by oneskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to oneskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

The compounds of Formulas (I), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) can besynthesized by one skilled in the art following the methods and examplesdescribed herein. The synthesis of the parent COX-2 inhibitors (i.e.non-nitrosated and/or non-nitrosylated COX-2 inhibitors) are disclosedin, for example, U.S. Pat. Nos. 5,344,991, 5,393,790, 5,466,823,5,474,995, 5,486,534, 5,504,215, 5,508,426, 5,510,496, 5,516,907,5,521,207, 5,536,752, 5,550,142, 5,563,165, 5,616,601, 5,620,999,5,677,318, 5,668,161, 5,691,374, 5,698,584, 5,710,140, 5,753,688,5,859,257, 5,908,858, 5,945,539, 5,994,381, 6,080,876, 6,083,969 and6,071,954 and in WO 91/19708, WO 94/15932, WO 94/26731, WO 94/27980, WO95/00501, WO 95/11883, WO 95/15315, WO 95/15316, WO 95/15317, WO95/15318, WO 95/18799, WO 95/21817, WO 95/30652, WO 96/30656, WO96/03387, WO 96/03392, WO 96/03385, WO 96/03387, WO 96/03388, WO96/09293, WO 96/09304, WO 96/16934, WO 96/19462, WO 96/19463, WO96/19469, WO 96/25405, WO 96/36617, WO 96/36623, WO 97/11704, WO97/13755, WO 97/27181, WO 97/14691, WO 97/16435, WO 97/34882, WO97/36863, WO 97/40012, WO 97/45420, WO 98/00416, WO 98/11080, WO98/22422, WO 98/41516, WO 98/46594, WO 98/52937, WO 99/15531, WO99/23087, WO 99/33796, WO 99/25695, WO 99/61016, WO 99/62884 and WO99/64415 and in EP 0 745 596 A1, EP 0 087 629 B1, EP 0 418 845 B1, EP 0554 829 A2, EP 0 863 134 A1, EP 1 006 114 A1 for the parent compounds ofFormulas (I) and (II); and in U.S. Pat. Nos. 5,733,909, 5,789,413 and5,849,943 and in WO 96/13483, WO 97/28120 and WO 97/28121 for the parentcompounds of Formula (III); and in U.S. Pat. Nos. 5,861,419 and6,001,843 and in WO 96/10012, WO 96/16934, WO 96/24585, WO 98/03484, WO98/24584, WO 98/47871, WO 99/14194 and WO 99/14195 for the parentcompounds of Formula (IV); and in U.S. Pat. Nos. 5,436,265, 5,510,368,5,604,253 and 5,639,780 and in WO 96/37467, WO 96/37468, WO 96/37469, WO98/39330 and WO 00/40087 for the parent compounds of Formula (V); and inU.S. Pat. Nos. 5,409,9444, 5,604,260, 5,968,859, 5,776,984, 5,968,958and in WO 94/13635, WO 94/20480, WO 96/23786, WO 97/03953, WO 98/33769and WO 99/15503 for the parent compounds of Formula (VI); and in WO98/41511, WO 99/10331, WO 99/10332 and WO 00/24719 for the parentcompounds of Formula (VII); and in WO 98/47890 and WO 00/23443 for theparent compounds of Formula (VIII), and in U.S. Pat. No. 5,807,873 andWO 98/43966 for the parent compounds of Formula (IX); and in U.S. Pat.Nos. 5,521,213 and 5,552,422 and in WO 96/06840, WO 96/21667, WO96/31509, WO 99/12930, WO 00/08024 and WO 00/26216 for the parentcompounds of Formula (X); and in U.S. Pat. Nos. 5,776,967, 5,824,699 and5,830,911 and in WO 98/04527 for the parent compounds of Formula (XI);and in U.S. Pat. Nos. 5,750,558 and 5,756,531 and in WO 97/41100, WO98/05639, WO 98/21195, WO 98/57924, WO 99/05104 and WO 99/35130 for theparent compounds of Formula (XII); and in WO 99/61436 for the parentcompounds of Formula (XIII); and in WO 00/10993 for the parent compoundsof Formula (XIV); and in WO 98/32732 for the parent compounds of Formula(XV); and in WO 97/09977, WO 99/11605 and WO 99/41224 for the parentcompounds of Formula (XVI); the disclosures of each of which areincorporated by reference herein in their entirety. The parent COX-2inhibitor compounds can then be nitrosated and/or nitrosylated throughone or more sites such as oxygen, sulfur and/or nitrogen using themethods described in the examples herein and using conventional methodsknown to one skilled in the art. For example, known methods fornitrosating and nitrosylating compounds are described in U.S. Pat. Nos.5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae et al, Org.Prep. Proc. Int., 15(3):165-198 (1983), the disclosures of each of whichare incorporated by reference herein in their entirety. The methods ofnitrosating and/or nitrosylating the compounds described in the examplesherein and in these references can be applied by one skilled in the artto produce any of the nitrosated and/or nitrosylated COX-2 inhibitorsdescribed herein.

The compounds of the present invention include the parent COX-2inhibitors, including those described herein, which have been nitrosatedand/or nitrosylated through one or more sites such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation) and/or nitrogen. Thenitrosated and/or nitrosylated COX-2 inhibitors of the present inventiondonate, transfer or release a biologically active form of nitrogenmonoxide (i.e., nitric oxide).

Nitrogen monoxide can exist in three forms: NO− (nitroxyl), NO•(uncharged nitric oxide) and NO⁺ (nitrosonium). NO• is a highly reactiveshort-lived species that is potentially toxic to cells. This is criticalbecause the pharmacological efficacy of NO depends upon the form inwhich it is delivered. In contrast to the nitric oxide radical (NO•),nitrosonium (NO⁺) does not react with O₂ or O₂ ⁻ species, andfunctionalities capable of transferring and/or releasing NO⁺ and NO− arealso resistant to decomposition in the presence of many redox metals.Consequently, administration of charged NO equivalents (positive and/ornegative) is a more effective means of delivering a biologically activeNO to the desired site of action.

Compounds contemplated for use in the present invention (e.g.,nitrosated and/or nitrosylated COX-2 inhibitors) are, optionally, usedin combination with nitric oxide and compounds that release nitric oxideor otherwise directly or indirectly deliver or transfer a biologicallyactive form of nitrogen monoxide to a site of its intended activity,such as on a cell membrane in vivo.

The term “nitric oxide” encompasses uncharged nitric oxide (NO•) andcharged nitrogen monoxide species, preferably charged nitrogen monoxidespecies, such as nitrosonium ion (NO⁺) and nitroxyl ion (NO−). Thereactive form of nitric oxide can be provided by gaseous nitric oxide.The nitrogen monoxide releasing, delivering or transferring compoundshave the structure F—NO, wherein F is a nitrogen monoxide releasing,delivering or transferring moiety, and include any and all suchcompounds which provide nitrogen monoxide to its intended site of actionin a form active for its intended purpose. The term “NO adducts”encompasses any nitrogen monoxide releasing, delivering or transferringcompounds, including, for example, S-nitrosothiols, nitrites, nitrates,S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines, (NONOates),(E)-alkyl-2-[(E)-hydroxyimino]-5nitro-3-hexene amines or amides,nitrosoamines, furoxans as well as substrates for the endogenous enzymeswhich synthesize nitric oxide. The “NO adducts” can bemono-nitrosylated, poly-nitrosylated, mono-nitrosated and/orpoly-nitrosated at a variety of naturally susceptible or artificiallyprovided binding sites for biologically active forms of nitrogenmonoxide.

One group of NO adducts is the S-nitrosothiols, which are compounds thatinclude at least one —S—NO group. These compounds includeS-nitroso-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); S-nitrosylated amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixturesand derivatives thereof); S-nitrosylated sugars S-nitrosylated, modifiedand unmodified, oligonucleotides (preferably of at least 5, and morepreferably 5-200 nucleotides); straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedS-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.S-nitrosothiols and methods for preparing them are described in U.S.Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. Proc. Int., 15(3):165-198 (1983), the disclosures of eachof which are incorporated by reference herein in their entirety.

Another embodiment of the present invention is S-nitroso amino acidswhere the nitroso group is linked to a sulfur group of asulfur-containing amino acid or derivative thereof. Such compoundsinclude, for example, S-nitroso—N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine, S-nitroso-glutathione, S-nitroso-cysteinyl-glycine,and the like.

Suitable S-nitrosylated proteins include thiol-containing proteins(where the NO group is attached to one or more sulfur groups on an aminoacid or amino acid derivative thereof) from various functional classesincluding enzymes, such as tissue-type plasminogen activator (TPA) andcathepsin B; transport proteins, such as lipoproteins; heme proteins,such as hemoglobin and serum albumin; and biologically protectiveproteins, such as immunoglobulins, antibodies and cytokines. Suchnitrosylated proteins are described in WO 93/09806, the disclosure ofwhich is incorporated by reference herein in its entirety. Examplesinclude polynitrosylated albumin where one or more thiol or othernucleophilic centers in the protein are modified.

Other examples of suitable S-nitrosothiols include:

(i) HS(C(R_(e))(R_(f)))_(mm)SNO;

(ii) ONS(C(R_(e))(R_(f)))_(mm)R_(e); and

(iii) H₂N—CH(CO₂H)—(CH₂)_(mm)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H;

wherein mm is an integer from 2 to 20; R_(e) and R_(f) are eachindependently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy,an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an alkoxy, an aryl, an arylalkyl, a carboxamido, aalkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, acarbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, analkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, asulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl,an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a carbamoyl, aurea, a nitro, —T—Q—, or (C(R_(e))(R_(f)))_(k)—T—Q, or R_(e) and R_(f)taken together are an oxo, a methanthial, a heterocyclic ring, acycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO₂; and Tis independently a covalent bond, a carbonyl, an oxygen, —S(O)_(o)— or—N(R_(a))R_(i)—, wherein o is an integer from 0 to 2, R_(a) is a lonepair of electrons, a hydrogen or an alkyl group; R_(i) is a hydrogen, analkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, anarylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, analkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl,a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, anaminoaryl, —CH₂—C(T—Q)(R_(e))(R_(f)), or —(N₂O₂—)⁻•M⁺, wherein M⁺ is anorganic or inorganic cation; with the proviso that when R_(i) is—CH₂—C(T—Q)(R_(e))(R_(f)) or —(N₂O₂—)·M⁺; then “—T—Q” can be a hydrogen,an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxygroup or an aryl group.

In cases where R_(e) and R_(f) are a heterocyclic ring or taken togetherR_(e) and R_(f) are a heterocyclic ring, then R_(i) can be a substituenton any disubstituted nitrogen contained within the radical wherein R_(i)is as defined herein.

Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) which yields the S-nitrosoderivative. Acids which can be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. The thiol precursor can also benitrosylated by reaction with an organic nitrite such as tert-butylnitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate inan inert solvent.

Another group of NO adducts for use in the present invention, where theNO adduct is a compound that donates, transfers or releases nitricoxide, include compounds comprising at least one ON—O—, ON—N— or ON—C—group. The compounds that include at least one ON—O—, ON—N— or ON—C—group are preferably ON—O—, ON—N— or ON—C-polypeptides (the term“polypeptide” includes proteins and polyamino acids that do not possessan ascertained biological function, and derivatives thereof); ON—O—,ON—N— or ON—C-amino acids (including natural and synthetic amino acidsand their stereoisomers and racemic mixtures); ON—O—, ON—N— orON—C-sugars; ON—O—, ON—N— or ON—C— modified or unmodifiedoligonucleotides (comprising at least 5 nucleotides, preferably 5-200nucleotides); ON—O—, ON—N— or ON—C— straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and ON—O—, ON—N— or ON—C-heterocyclic compounds.

Another group of NO adducts for use in the present invention includenitrates that donate, transfer or release nitric oxide, such ascompounds comprising at least one O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C—group. Preferred among these compounds are O₂N—O₂N—N—, O₂N—S— or O₂N—C—polypeptides (the term “polypeptide” includes proteins and alsopolyamino acids that do not possess an ascertained biological function,and derivatives thereof); O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— amino acids(including natural and synthetic amino acids and their stereoisomers andracemic mixtures); O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C-sugars; O₂N—O—,O₂N—N—, O₂N—S— or O₂N—C— modified and unmodified oligonucleotides(comprising at least 5 nucleotides, preferably 5-200 nucleotides);O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— heterocycliccompounds. Preferred examples of compounds comprising at least oneO₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— group include isosorbide dinitrate,isosorbide mononitrate, clonitrate, erythrityltetranitrate, mannitolhexanitrate, nitroglycerin, pentaerythritoltetranitrate andpentrinitrol. Preferred are those —S—NO₂ compounds that are polypeptidesor hydrocarbons with a pair or pairs of thiols that are sufficientlystructurally proximate, i.e., vicinal, that the pair of thiols will bereduced to a disulfide. Compounds which form disulfide species releasenitroxyl ion (NO−) and uncharged nitric oxide (NO•). Compounds where thethiol groups are not sufficiently close to form disulfide bridgesgenerally provide nitric oxide as the NO− form and not as the unchargedNO• form.

Another group of such adducts are N-oxo-N-nitrosoamines which donate,transfer or release nitric oxide and are represented by the formula:

R¹R²N—N(O—M⁺)—NO,

where R¹ and R² are each independently a polypeptide, an amino acid, asugar, a modified or unmodified oligonucleotide, a straight or branched,saturated or unsaturated, aliphatic or aromatic, substituted orunsubstituted hydrocarbon, or a heterocyclic group, and where M⁺ is anorganic or inorganic cation, such as, for example, an alkyl substitutedammonium cation or a Group I metal cation.

The present invention is also directed to compounds that stimulateendogenous NO or elevate levels of endogenous endothelium-derivedrelaxing factor (EDRF) in vivo or are substrates for nitric oxidesynthase. Such compounds include, for example, L-arginine,L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated andnitrosylated analogs (e.g., nitrosated L-arginine, nitrosylatedL-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylatedL-homoarginine), precursors of L-arginine and/or physiologicallyacceptable salts thereof, including, for example, citrulline, ornithineor glutamine, inhibitors of the enzyme arginase (e.g.,N-hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid) and thesubstrates for nitric oxide synthase, cytokines, adenosin, bradykinin,calreticulin, bisacodyl, and phenolphthalein. EDRF is a vascularrelaxing factor secreted by the endothelium, and has been identified asnitric oxide (NO) or a closely related derivative thereof (Palmer et al,Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA,84:9265-9269 (1987)).

Another embodiment of the present invention provides compositionscomprising at least one parent COX-2 inhibitor and at least one compoundthat donates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. The parent COX-2 inhibitors includes any of those described inthe prior art, including those described in the patents and publicationscited herein, as well as the novel compounds described herein.

The present invention is also based on the discovery that compounds andcompositions of the present invention may also be used in conjunctionwith other therapeutic agents for co-therapies, partially or completely,in place of other conventional antiinflammatory compounds, such as, forexample, together with steroids, NSAIDs, 5-lipoxygenase (5-LO)inhibitors, leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄(LTA₄) hydrolase inhibitors, 5-HT agonists, HMG-CoA inhibitors, H₂receptor antagonists, antineoplastic agents, antiplatelet agents,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and mixtures thereof.

Leukotriene A₄ (LTA₄) hydrolase inhibitors refers to compounds thatselectively inhibit leukotriene A₄ hydrolase with an IC₅₀ of less thanabout 10 μM, and more preferably with an IC₅₀ of less than about 1 μM.Suitable LTA₄ hydrolase inhibitors include, but are not limited to,RP-64966, (S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric-acidbenzyl ester (Scripps Res. Inst.),N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine(Searle), 7-(4-(4-ureidobenzyl)phenyl) heptanoic acid (Rhone-PoulencRorer), and 3 (3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithiumsalt (Searle), and mixtures thereof.

Suitable LTB₄ receptor antagonists include, but are not limited to,ebselen, linazolast, ontazolast; WAY 121006 (American Home Products);Bay-x-1005 (Bayer); BI-RM-270 (Boehringer Ingleheim); CGS-25019C (CibaGeigy); ETH-615 (Leo Denmark); MAFP (Merck); TMK-688 (Terumo); T-0757(Tanabe); LY 213024, LY 210073, LY 223982, LY 233469, LY 255283, LY264086, LY 292728 and LY 293111 (Eli Lilly); ONO-LB457, ONO-4057, andONO-LB-448 (ONO), S-2474, calcitrol (Shionogi); PF 10042 (PerduFrederick); Pfizer 105696 (Pfizer Inc.); RP 66153 (Rhone-Poulenc);SC-53228, SC-41930, SC-50605, SC-51146 and SC-53228 (Searle); SB-201146and SB-209247 (SmithKline Beecham); SKF-104493 (SmithKline & French); SM15178 (Sumitamo); TMK-688 (Terumo); BPC 15, (Warner Lambert); andmixtures thereof. The preferred LTB₄ receptor antagonists are calcitrol,ebselen, Bay-x-1005, CGS-25019C, ETH-615, LY-293111, ONO-4057 andTMK-688, and mixtures thereof.

Suitable 5-LO inhibitors include, but are not limited to, A-76745, 78773and ABT761 (Abbott compounds); Bay-x-1005 (Bayer); CMI-392 (Cytomed);E-3040 (Eisai); EF-40 (Scotia Pharmaceutical); F-1322 (Fujirebio);ML-3000 (Merckle); PF-5901 (Purdue Frederick); R-840 (3MPharmaceuticals); rilopirox, flobufen, linasolast, lonapolene,masoprocol, ontasolast, tenidap, zileuton, pranlukast, tepoxalin,rilopirox, flezelastine hydrochloride, enazadrem phosphate, andbunaprolast, and mixtures thereof. Suitable 5-LO inhibitors are alsodescribed more fully in WO 97/29776 assigned to G.D. Searle & Co.

Suitable 5-HT agonists, include, but are not limited to, rizatriptan,sumatriptan, naratriptan, zolmitroptan, eleptriptan, almotriptan, ergotalkaloids. ALX 1323, Merck L 741604 SB 220453 and LAS 31416. Suitable5-HT agonists are described more fully in WO 0025779, assigned to Merck& Co., Inc and in WO 00/48583, assigned to Pozen Inc. 5-HT agonistsrefers to a compound that is an agonist to any 5-HT receptor, includingbut not limited to, 5-HT₁ agonists, 5-HT_(1B) agonists and 5-HT_(1D)agonists.

Suitable steroids, include, but are not limited to, budesonide,dexamethasone, corticosterone, prednisolone, and the like. Suitablesteroids are described more fully in the literature, such as in theMerck Index on CD-ROM, Twelfth Edition, Version 12:1, 1996.

Suitable HMG CoA inhibitors, include, but are not limited to, reductaseand synthase inhibitors, such as, for example, squalene synthetaseinhibitors, benzodiazepine squalene synthase inhibitors, squaleneepoxidase inhibitors, acylcoenzyme A, bile acid sequestrants,cholesterol absorption inhibitors, and the like.

Suitable NSAIDs, include, but are not limited to, acetaminophen,aspirin, diclofenac, ibuprofen, ketoprofen, naproxen and the like.Suitable NSAIDs are described more fully in the literature, such as inGoodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1995, Pgs. 617-657; and the Merck Index onCD-ROM, Twelfth Edition, Version 12:1, 1996.

Suitable H₂ receptor antagonists, include, but are not limited to,cimetidine, roxatidine, rantidine and the like. Suitable H₂ receptorantagonists are described more fully in the literature, such as inGoodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1995, Pgs. 901-915; and the Merck Index onCD-ROM, Twelfth Edition, Version 12:1, 1996.

Suitable antineoplastic agents, include but are not limited to,5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, altretamine,anaxirone, aclarubicin and the like. Suitable antineoplastic agents arealso described more fully in U.S. Pat. No. 6,025,353 and WO 00/38730assigned to G.D. Searle & Co.

Suitable antiplatelet agents, include but are not limited to, aspirin,ticlopidine, dipyridamole, clopidogrel, glycoprotein lIb/IIIa receptorantagonists, and the like.

Suitable decongestants include, but are not limited to, phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, levo-desoxyephedrine, andthe like.

Suitable antitussives include, but are not limited to, codeine,hydrocodone, caramiphen, carbetapentane, dextramethorphan, and the like.

Suitable proton pump inhibitors, include, but are not limited to,omeprazole, lansoprazole, rabeprazole, pantoprazole, and the like.Suitable proton pump inhibitors are described more fully in theliterature, such as in Goodman and Gilman, The Pharmacological Basis ofTherapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901-915; and theMerck Index on CD-ROM, Twelfth Edition, Version 12:1, 1996.

The compounds and compositions of the present invention, may also beused in combination therapies with opioids and other analgesics,including, but not limited to, narcotic analgesics, Mu receptorantagonists, Kappa receptor antagonists, non-narcotic (i.e.non-addictive) analgesics, monoamine uptake inhibitors, adenosineregulating agents, cannabinoid derivatives, neurokinin 1 receptorantagonists, Substance P antagonists, neurokinin-1 receptor antagonists,sodium channel blockers, N-methyl-D-aspartate receptor antagonists, andmixtures thereof. Preferred combination therapies would be withmorphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol,dezocine, meptazinol, hydrocodone, oxycodone, methadone, Tramadol ((+)enantiomer), DuP 747, Dynorphine A, Enadoline, RP-60180, HN-11608,E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene,nalbuphine, E-4018, filenadol, mirtentanil, amitriptyline, DuP631,Tramadol ((−) enantiomer), GP-531, acadesine, AKI-1, AKI-2, GP-1683,GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742,SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, CP-99,994, and mixturesthereof.

The compounds and compositions of the present invention can also be usedin combination with inducible nitric oxide synthase (iNOS) inhibitors.Suitable iNOS inhibitors are disclosed in U.S. Pat. Nos. 5,132,453 and5,273,875, and in WO 97/38977 and WO 99/18960, the disclosures of eachof which are incorporated by reference herein in their entirety.

The present invention is also based on the discovery that theadministration of a therapeutically effective amount of the compoundsand compositions described herein is effective for treatinginflammation, pain (both chronic and acute), and fever, such as, forexample, analgesic in the treatment of pain, including, but not limitedto headaches, migraines, postoperative pain, dental pain, muscular pain,and pain resulting from cancer; as an antipyretic for the treatment offever, including but not limited to, rheumatic fever, symptomsassociated with influenza or other viral infections, common cold, lowback and neck pain, dysmenorrhea, headache, toothache, sprains, strains,myositis, neuralgia, synovitis; arthritis, including but not limited torheumatoid arthritis, degenerative joint disease (osteoarthritis),spondyloarthropathies, gouty arthritis, systemic lupus erythematosus andjuvenile arthritis. For example, the patient can be administered atherapeutically effective amount of at least one nitrosated and/ornitrosylated COX-2 inhibitor of the present invention. In anotherembodiment, the patient can be administered a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated COX-2 inhibitorand at least one compound that donates, transfers or releases nitricoxide, or elevates levels of endogenous EDRF or nitric oxide, or is asubstrate for nitric oxide synthase. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one nitrosated and/or nitrosylated COX-2 inhibitor, and, at leastone therapeutic agent, including but not limited to, steroids,nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO)inhibitors, leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄(LTA₄) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, decongestants, diuretics, sedating or non-sedatinganti-histamines, inducible nitric oxide synthase inhibitors, opioids,analgesics, Helicobacter pylori inhibitors, proton pump inhibitors,isoprostane inhibitors, and, optionally, at least one compound thatdonates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. The compounds can be administered separately or in the form ofa composition.

Another embodiment of the invention provides methods for decreasingand/or preventing gastrointestinal disorders and improving thegastrointestinal properties of the parent COX-2 inhibitor (i.e.,non-nitrosated and/or non-nitrosylated COX-2 inhibitor) by administeringto the patient in need thereof a therapeutically effective amount of thecompounds and/or compositions described herein. Such gastrointestinaldisorders refer to any disease or disorder of the upper gastrointestinaltract (e.g., esophagus, stomach, duodenum and jejunum) including, forexample, inflammatory bowel disease, Crohn's disease, gastritis,irritable bowel syndrome, ulcerative colitis, peptic ulcers, stressulcers, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease, bacterialinfections (including, for example, a Helicobacter pylori associateddisease), short-bowel (anastomosis) syndrome, hypersecretory statesassociated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia, and bleeding peptic ulcers that result, for example,from neurosurgery, head injury, severe body trauma or burns. Forexample, the patient can be administered a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated COX-2 inhibitor ofthe present invention. In another embodiment, the patient can beadministered a therapeutically effective amount of at least onenitrosated and/or nitrosylated COX-2 inhibitor and at least one compoundthat donates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. In yet another embodiment, the patient can be administered atherapeutically effective amount of at least one nitrosated and/ornitrosylated COX-2 inhibitor and at least one therapeutic agent,including but not limited to, steroids, nonsteroidal antiinflammatorycompounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄(LTB₄) receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors,5-HT agonists, 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)inhibitors, H₂ antagonists, antineoplastic agents, antiplatelet agents,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and, optionally, at least one compound that donates,transfers or releases nitric oxide, or elevates levels of endogenousEDRF or nitric oxide, or is a substrate for nitric oxide synthase. Thecompounds can be administered separately or in the form of acomposition.

Yet another embodiment of the invention provides methods forfacilitating wound healing (such as, for example, ulcer healing) byadministering to the patient in need thereof a therapeutically effectiveamount of the compounds and/or compositions described herein. Woundrefers to, and includes, any lesion that is characterized by loss oftissue, and, includes, but is not limited to, ulcers, cuts, burns, andthe like. Ulcers refers to lesions of the upper gastrointestinal tractlining that are characterized by loss of tissue, and, include, but arenot limited to, gastric ulcers, duodenal ulcers, gastritis, and thelike. For example, the patient can be administered a therapeuticallyeffective amount of at least one nitrosated and/or nitrosylated COX-2inhibitor of the present invention. In another embodiment, the patientcan be administered a therapeutically effective amount of at least onenitrosated and/or nitrosylated COX-2 inhibitor and at least one nitricoxide donor. In yet another embodiment, the patient can be administereda therapeutically effective amount of at least one nitrosated and/ornitrosylated COX-2 inhibitor and at least one therapeutic agent, and,optionally, at least one nitric oxide donor. The compounds can beadministered separately or in the form of a composition.

Another embodiment of the invention provides methods to decrease orreverse renal and other toxicities (such as, for example, kidneytoxicity) by administering to a patient in need thereof atherapeutically effective amount of the compounds and/or compositionsdescribed herein. For example, the patient can be administered atherapeutically effective amount of at least one nitrosated and/ornitrosylated COX-2 inhibitor of the present invention. In anotherembodiment, the patient can be administered a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated COX-2 inhibitorand at least one nitric oxide donor. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one nitrosated and/or nitrosylated COX-2 inhibitor and at leastone therapeutic agent, and, optionally, at least one nitric oxide donor.The compounds can be administered separately or in the form of acomposition.

Another embodiment of the invention provides methods to treat or preventdisorders resulting from elevated levels of COX-2 by administering to apatient in need thereof a therapeutically effective amount of thecompounds and/or compositions described herein. For example, the patientcan be administered a therapeutically effective amount of at least onenitrosated and/or nitrosylated COX-2 inhibitor of the present invention.In another embodiment, the patient can be administered a therapeuticallyeffective amount of at least one nitrosated and/or nitrosylated COX-2inhibitor and at least one compound that donates, transfers or releasesnitric oxide, or elevates levels of endogenous EDRF or nitric oxide, oris a substrate for nitric oxide synthase. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one nitrosated and/or nitrosylated COX-2 inhibitor and at leastone therapeutic agent, including but not limited to, steroids, anonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO)inhibitors, leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄(LTA₄) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, decongestants, diuretics, sedating or non-sedatinganti-histamines, inducible nitric oxide synthase inhibitors, opioids,analgesics, Helicobacter pylori inhibitors, proton pump inhibitors,isoprostane inhibitors, and, optionally, at least one compound thatdonates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. The compounds can be administered separately or in the form ofa composition.

Disorders resulting from elevated levels of COX-2 (e.g., COX-2 mediateddisorders) include, but are not limited to, for example, angiogenesis,arthritis, asthma, bronchitis, menstrual cramps, premature labor,tendinitis, bursitis; skin-related conditions, such as, for example,psoriasis, eczema, surface wounds, burns and dermatitis; post-operativeinflammation including from ophthalmic surgery, such as, for example,cataract surgery and refractive surgery, and the like; treatment ofneoplasia, such as, for example, brain cancer, bone cancer, epithelialcell-derived neoplasia (epithelial carcinoma), such as, for example,basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, such as,for example, lip cancer, mouth cancer, esophageal cancer, small bowelcancer and stomach cancer, colon cancer, liver cancer, bladder cancer,pancreas cancer, ovary cancer, cervical cancer, lung cancer, breastcancer and skin cancer, such as squamus cell and basal cell cancers,prostate cancer, renal cell carcinoma, and other known cancers thateffect epithelial cells throughout the body, benign and canceroustumors, growths, polyps, adenomatous polyps, including, but not limitedto, familial adenomatous polyposis, fibrusis resulting from radiationtherapy, and the like; treatment of inflammatory processes in diseases,such as, for example, vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, neuromuscular junctiondisease including myasthenia gravis, white matter disease includingmultiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, nephritis, hypersensitivity, swellingoccurring after injury, myocardial ischemia, and the like; treatment ofophthalmic diseases and disorders, such as, for example, retinitis,retinopathies, uveitis, ocular photophobia, acute injury to the eyetissue, glaucoma, inflammation of the eye and elevation of intraocularpressure and the like; treatment of pulmonary inflammation, such as, forexample, those associated with viral infections and cystic fibrosis, andthe like; treatment of certain central nervous system disorders, suchas, for example, cortical dementias including Alzheimer's disease,vascular dementia, multi-infarct dementia, pre-senile dementia,alcoholic dementia, senile dementia, and central nervous system damageresulting from stroke, ischemia and trauma, and the like; treatment ofallergic rhinitis, respiratory distress syndrome, endotoxin shocksyndrome, atherosclerosis; treatment of inflammations and/or microbialinfections including, for example, inflammations and/or infections ofthe eyes, ears, nose, throat, and/or skin; treatment and/or preventionof cardiovascular disorders, such as, for example, coronary arterydisease, aneurysm, arteriosclerosis, atherosclerosis, including, but notlimited to, cardiac transplant atherosclerosis, myocardial infarction,ischemia, embolism, stroke, thrombosis, hypertension, venous thrombosis,thromboembolism, thrombotic occlusion and reclusion, restenosis, angina,unstable angina, shock, heart failure, coronary plaque inflammation,bacterial-induced inflammation, such as, for example, Chlamydia-inducedinflammation, viral induced inflammation, inflammation associated withsurgical procedures, such as, for example, vascular grafting, coronaryartery bypass surgery, revascularization procedures, such as, forexample, angioplasty, stent placement, endarterectomy, vascularprocedures involving arteries, veins, capillaries, and the like;treatment and/or prevention of urinary and/or urological disorders, suchas, for example, incontinence and the like; treatment and/or preventionof endothelial dysfunctions, such as, for example, diseases accompanyingthese dysfunctions, endothelial damage from hypercholesterolemia,endothelial damage from hypoxia, endothelial damage from mechanical andchemical noxae, especially during and after drug, and mechanicalreopening of stenosed vessels, for example, following percutaneoustransluminal angiography (PTA) and percuntaneous transluminal coronaryangiography (PTCA), endothelial damage in postinfarction phase,endothelium-mediated reocclusion following bypass surgery, blood supplydisturbances in peripheral arteries, as well as, cardiovasculardiseases, and the like; preservation of organs and tissues, such as, forexample, for organ transplants, and the like; inhibition and/orprevention of activation, adhesion and infiltration of neutrophils atthe site of inflammation; inhibition and/or prevention of plateletaggregation. The compounds and compositions of the present invention canalso be used as a pre-anesthetic medication in emergency operations toreduce the danger of aspiration of acidic gastric contents.

When administered in vivo, the compounds and compositions of the presentinvention can be administered in combination with pharmaceuticallyacceptable carriers and in dosages described herein. When the compoundsand compositions of the present invention are administered as a mixtureof at least one nitrosated and/or nitrosylated COX-2 inhibitor and atleast one nitric oxide donor and/or therapeutic agent, they can also beused in combination with one or more additional compounds which areknown to be effective against the specific disease state targeted fortreatment. The nitric oxide donors, therapeutic agents and/or otheradditional compounds can be administered simultaneously with,subsequently to, or prior to administration of the nitrosated and/ornitrosylated COX-2 inhibitor.

Another embodiment of the present invention provides methods fortreating inflammation, pain and fever; for treating and/or improving thegastrointestinal properties of COX-2 inhibitors; for facilitating woundhealing; for treating and/or preventing renal toxicity; and for treatingand/or preventing other cyclooxygenase-2 mediated disorders comprisingadministration of at least one parent COX-2 inhibitor and at least onenitric oxide donor, and, optionally, at least one therapeutic agent. Forexample, the patient can be administered a therapeutically effectiveamount of at least one parent COX-2 inhibitor of the present inventionand at least one nitric oxide donor. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one parent COX-2 inhibitor, at least one nitric oxide donor and atleast one therapeutic agent. The compounds can be administeredseparately or in the form of a composition.

The compounds and compositions of the present invention can beadministered by any available and effective delivery system including,but not limited to, orally, bucally, parenterally, by inhalation spray,by topical application, by injection, transdermally, or rectally (e.g.,by the use of suppositories) in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles, as desired. Parenteral includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

Transdermal compound administration, which is known to one skilled inthe art, involves the delivery of pharmaceutical compounds viapercutaneous passage of the compound into the systemic circulation ofthe patient. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Other components can be incorporated into the transdermalpatches as well. For example, compositions and/or transdermal patchescan be formulated with one or more preservatives or bacteriostaticagents including, but not limited to, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.Dosage forms for topical administration of the compounds andcompositions can include creams, sprays, lotions, gels, ointments, eyedrops, nose drops, ear drops, and the like. In such dosage forms, thecompositions of the invention can be mixed to form white, smooth,homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1%or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropylpalmitate, lactic acid, purified water and sorbitol solution. Inaddition, the compositions can contain polyethylene glycol 400. They canbe mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt)as preservative, white petrolatum, emulsifying wax, and tenox II(butylated hydroxyanisole, propyl gallate, citric acid, propyleneglycol). Woven pads or rolls of bandaging material, e.g., gauze, can beimpregnated with the compositions in solution, lotion, cream, ointmentor other such form can also be used for topical application. Thecompositions can also be applied topically using a transdermal system,such as one of an acrylic-based polymer adhesive with a resinouscrosslinking agent impregnated with the composition and laminated to animpermeable backing.

Solid dosage forms for oral administration can include capsules,tablets, effervescent tablets, chewable tablets, pills, powders,sachets, granules and gels. In such solid dosage forms, the activecompounds can be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms can also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, effervescent tablets, and pills, the dosage forms can alsocomprise buffering agents. Soft gelatin capsules can be prepared tocontain a mixture of the active compounds or compositions of the presentinvention and vegetable oil. Hard gelatin capsules can contain granulesof the active compound in combination with a solid, pulverulent carriersuch as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives of gelatin. Tablets and pillscan be prepared with enteric coatings.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

Suppositories for vaginal or rectal administration of the compounds andcompositions of the invention, such as for treating pediatric fever andthe like, can be prepared by mixing the compounds or compositions with asuitable nonirritating excipient such as cocoa butter and polyethyleneglycols which are solid at room temperature but liquid at rectaltemperature, such that they will melt in the rectum and release thedrug.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution or suspension in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that can be used are water,Ringer's solution, and isotonic sodium chloride solution. Sterile fixedoils are also conventionally used as a solvent or suspending medium.

The compositions of this invention can further include conventionalexcipients, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral application which do notdeleteriously react with the active compounds. Suitable pharmaceuticallyacceptable carriers include, for example, water, salt solutions,alcohol, vegetable oils, polyethylene glycols, gelatin, lactose,amylose, magnesium stearate, talc, surfactants, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,petroethral fatty acid esters, hydroxymethylcellulose,polyvinylpyrrolidone, and the like. The pharmaceutical preparations canbe sterilized and if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringand/or aromatic substances and the like which do not deleteriously reactwith the active compounds. For parenteral application, particularlysuitable vehicles consist of solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. Aqueoussuspensions may contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethyl cellulose,sorbitol and/or dextran. Optionally, the suspension may also containstabilizers.

The composition, if desired, can also contain minor amounts of wettingagents, emulsifying agents and/or pH buffering agents. The compositioncan be a liquid solution, suspension, emulsion, tablet, pill, capsule,sustained release formulation, or powder. The composition can beformulated as a suppository, with traditional binders and carriers suchas triglycerides. Oral formulations can include standard carriers suchas pharmaceutical grades of mannitol, lactose, starch, magnesiumstearate, sodium saccharine, cellulose, magnesium carbonate, and thelike.

Various delivery systems are known and can be used to administer thecompounds or compositions of the present invention, including, forexample, encapsulation in liposomes, microbubbles, emulsions,microparticles, microcapsules and the like. The required dosage can beadministered as a single unit or in a sustained release form.

The bioavailability of the compositions can be enhanced by micronizationof the formulations using conventional techniques such as grinding,milling, spray drying and the like in the presence of suitableexcipients or agents such as phospholipids or surfactants.

The preferred methods of administration of the nitrosated and/ornitrosylated COX-2 inhibitor compositions or the parent COX-2 inhibitorfor the treatment of gastrointestinal disorders are orally, bucally orby inhalation. The preferred methods of administration for the treatmentof inflammation and microbial infections are orally, bucally, topically,transdermally or by inhalation.

The compounds and compositions of the present invention can beformulated as pharmaceutically acceptable salt forms. Pharmaceuticallyacceptable salts include, for example, alkali metal salts and additionsalts of free acids or free bases. The nature of the salt is notcritical, provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric and phosphoric acid and the like. Appropriateorganic acids include, but are not limited to, aliphatic,cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classesof organic acids, such as, for example, formic, acetic, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, toluenesulfonic,2-hydroxymethanesulphonic, sulfanilic, stearic, algenic,β-hydroxybutyric, cyclohexylaminosulfonic, galactaric and galacturonicacid and the like. Suitable pharmaceutically-acceptable base additionsalts include, but are not limited to, metallic salts made fromaluminum, calcium, lithium, magnesium, potassium, sodium and zinc ororganic salts made from primary, secondary and tertiary amines, cyclicamines, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine and the like. All of these salts may be prepared byconventional means from the corresponding compound by reacting, forexample, the appropriate acid or base with the compound.

While individual needs may vary, determination of optimal ranges foreffective amounts of the compounds and/or compositions is within theskill of the art. Generally, the dosage required to provide an effectiveamount of the compounds and compositions, which can be adjusted by oneof ordinary skill in the art, will vary depending on the age, health,physical condition, sex, diet, weight, extent of the dysfunction of therecipient, frequency of treatment and the nature and scope of thedysfunction or disease, medical condition of the patient, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound used, whether a drug delivery system is used, and whether thecompound is administered as part of a drug combination.

The amount of a given nitrosated and/or nitrosylated COX-2 inhibitor orthe parent COX-2 inhibitor which will be effective in the treatment of aparticular disorder or condition will depend on the nature of thedisorder or condition, and can be determined by standard clinicaltechniques, including reference to Goodman and Gilman, supra; ThePhysician's Desk Reference, Medical Economics Company, Inc., Oradell,N.J., 1995; and Drug Facts and Comparisons, Inc., St. Louis, Mo., 1993.The precise dose to be used in the formulation will also depend on theroute of administration, and the seriousness of the disease or disorder,and should be decided by the physician and the patient's circumstances.

The amount of nitric oxide donor in a pharmaceutical composition can bein amounts of about 0.1 to about 10 times the molar equivalent of theCOX-2 inhibitor. The usual daily doses of nitrosated and/or nitrosylatedCOX-2 inhibitors are about 0.001 mg to about 140 mg/kg of body weightper day, preferably 0.005 mg to 30 mg/kg per day, or alternatively about0.5 mg to about 7 g per patient per day. For example, inflammations maybe effectively treated by the administration of from about 0.01 mg to 50mg of the compound per kilogram of body weight per day, or alternativelyabout 0.5 mg to about 3.5 g per patient per day. The compounds may beadministered on a regimen of up to 6 times per day, preferably 1 to 4times per day, and most preferably once per day. Effective doses may beextrapolated from dose-response curves derived from in vitro or animalmodel test systems and are in the same ranges or less than as describedfor the commercially available compounds in the Physician's DeskReference, supra.

The present invention also provides pharmaceutical kits comprising oneor more containers filled with one or more of the ingredients of thepharmaceutical compounds and/or compositions of the present invention,including, at least, one or more of the COX-2 inhibitors optionallysubstituted with at least one NO and/or NO₂ group, described herein andone or more of the NO donors described herein. Associated with such kitscan be additional therapeutic agents or compositions (e.g., steroids,NSAIDs, 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists and leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, HMGCoA inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, decongestants, diuretics, sedating or non-sedatinganti-histamines, inducible nitric oxide synthase inhibitors, opioids,analgesics, Helicobacter pylori inhibitors, proton pump inhibitors,isoprostane inhibitors, and the like), devices for administering thecompositions, and notices in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticals orbiological products which reflects approval by the agency ofmanufacture, use or sale for humans.

EXAMPLES

The following non-limiting examples further describe and enable one ofordinary skill in the art to make and use the present invention. In eachof the examples, flash chromatography was performed on 40 micron silicagel (Baker).

Example 14-[5-(4-Chlorophenyl)-3-[(nitrooxy)methyl]-3-hydropyrazolyl]benzenesulfonamide1a.4-[5-(4-Chlorophenyl)-3-(hydroxymethyl)-3-hydropyrazolyl]benzenesulfonamide

This compound was synthesized as described by Penning et al, J. Med.Chem., 40: 1347-1365 (1997), (the disclosure of which is incorporated byreference herein in its entirety), Example 14a. ¹H NMR (300 MHz, CDCl₃)δ 7.87 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.7 Hz,2H), 7.15 (d, J=8.4 Hz, 2H), 6.54 (s, 1H), 4.79 (s, 2H)

1b.4-[5-(4-Chlorophenyl)-3-[(nitrooxy)methyl]-3-hydropyrazolyl]benzenesulfonamide

To a solution of the product of Example 1a (348 mg, 0.95 mmol) in EtOAc(10 mL) was added over 5 minutes at room temperature a mixture of HNO₃(85 μl, fuming 90%) in acetic anhydride (400 μL). The reaction wasstirred for 15 minutes at room temperature. The mixture was poured intoexcess aqueous Na₂CO₃. The aqueous layer was extracted with EtOAc. Thecombined organic layers were dried over NA₂SO₄ and concentrated. Theresidue was chromatographed on silica gel eluting with 2:1 Hex:EtOAc togive 210 mg (54%) of the title compound. ¹H NMR (300 MHz, CDCl₃) δ 7.90(d, J=8.2 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.15(d, J=8.5 Hz, 2H), 6.61 (s, 1H), 5.55 (s, 2H), 4.97 (s, 2H); ¹³C NMR (75MHz, CDCl₃) δ 146.2, 143.8, 142.4, 141.2, 135.4, 130.0, 129.2, 128.2,127.6, 127.5, 125.1, 109.2, 67.8.

Example 24-{5-[(Nitrooxy)methyl]-3-phenylisoxazol4-yl}benzenesulfonamide 2a.4-[5-(Hydroxymethyl)-3-phenylisoxazol-4-yl]benzenesulfonamide

This compound was synthesized as described in patent application WO96/25405, (the disclosure of which is incorporated by reference hereinin its entirety), Example 10. ¹H NMR (300 MHz, DMSO-d₆) δ 7.80 (d, J=8.3Hz, 2H), 7.32-7.45 (mult, 9H), 5.71 (t, J=5.3 Hz, 1H), 4.52 (d, J=4.5Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 69.5, 160.7, 143.5, 132.6, 130.1,129.8, 128.8, 128.3, 128.2, 126.0, 115.2, 53.3; mass spectrum (API-TIS),m/z 331 (MH⁺).

2b. 4-{5-[(Nitrooxy)methyl]-3-phenylisoxazol-4-yl}benzenesulfonamide

Concentrated HNO₃ (40 μL, 0.90 mmol) was added to stirred solution ofacetic anhydride (200 μL, 2.1 mmol) in EtOAc (0.3 mL) at 0° C. via asyringe and stirred for 5 minutes at 0° C. The product of Example 2a(0.1 g, 0.3 mmol) in EtOAc (0.1 mL) was then added and stirred for 5minutes at 0° C. The resulting mixture was then subjected to preparativethin layer chromatography (PTLC) eluting with 1:1 Hex:EtOAc to give thetitle compound (65 mg, 57%) as an oil. The oil was dissolved in CH₂Cl₂(5 mL) and solvent was evaporated slowly overnight at room temperatureto give the title compound as white crystals. mp 47-50° C. ¹H-NMR (300MHz, CDCl₃) δ 7.96 (d, J=8.4 Hz, 2H), 7.30-7.45 (mult, 7H), 5.49 (s,2H), 4.89 (br s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 161.4, 160.5, 142.3,133.0, 130.4, 130.3, 128.9, 128.4, 127.2, 127.1, 119.5, 62.7; massspectrum (API-TIS), m/z 376 (MH⁺)

Example 3 2-[1-Methyl-4-(nitrosothio)-4-piperidyl]ethyl3-(N-{[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl}carbamoyl)propanoatecitrate salt 3a. Ethyl 2-{1-methyl-4-piperidylidene}acetate

A solution of n-BuLi (1.6M in Hex, 58.7 mL, 93.6 mmol) was added to astirred solution of triethyl phosphonoacetate (17.5 g, 78.0 mmol) in THF(30 mL) at −78° C. under N₂. The resulting brownish solution was stirredfor 30 min and then a solution of 4-N-methylpiperidone (8.8 g, 78.0mmol) in THF (20 mL) was added. The cold bath was removed and themixture was stirred at room temperature for 2 hours. Water (250 mL) wasadded and the mixture was extracted with EtOAc (3×100 mL). The combinedorganic extracts were dried over NA₂SO₄. The solvent was evaporated toafford the title compound (13.2 g, 92%). ¹H NMR (300 MHz, CDCl₃) δ 5.64(s, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.00 (t, J=5.1 Hz, 10H), 2.32-2.53(mult, 5H), 2.29 (s, 3H), 1.27 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 1.664, 158.6, 114.2, 59.5, 56.7, 56.1, 45.7, 36.7, 29.3, 14.2.

3b. Ethyl 2-{1-methyl-4-(phenylmethylthio)piperidyl}acetate

The product of Example 3a (13.2 g, 72.01 mmol) and benzylmercaptan (8.4mL, 72.01 mmol) in piperidine (35 mL) were heated at 100° C. for 12hours and then cooled to room temperature. Water (50 mL) was added andthe aqueous layer was extracted with EtOAc (3×100 mL). The combinedorganic layers were dried over Na₂SO₄. The solvent was evaporated andthe residue was purified by chromatography on silica gel eluting with1:9 MeOH:CH₂Cl₂ to afford the title compound (11.7 g, 53%) as a viscousliquid. ¹H NMR (300 MHz, CDCl₃) δ 7.18-7.34 (mult, 5H), 4.17(q, J=7.1Hz, 2H), 3.71 (s, 2H), 2.64 (s, 2H), 2.46-2.54 (mult, 4H), 2.29 (s, 3H),1.83-1.95 (mult, 4H), 1.29 (t, J=7.1 Hz. 3H).

3c. 2-[1-Methyl-4-(phenylmethylthio)-4-piperidyl]ethan-1-ol

A solution of diisobutylaluminium hydride in hexane (83 mL, 83 mmol) wasadded to a stirred solution of the product of Example 3b (11.7 g, 38.74mmol) in THF (40 mL) at −78° C. under N₂. The cold bath was removed andthe mixture was stirred for 1.5 hours. Solid Na₂SO₄.10H₂O (3 g) wasadded portionwise with stirring until a thick precipitate was formed.10% MeOH in CH₂Cl₂ (100 mL) was added and the mixture was filtered. Thesolid was washed with additional 10% MeOH in CH₂Cl₂ (100 mL) and thesolvent was evaporated. The residue was chromatographed on silica geleluting with 1:9 MeOH:CH₂Cl₂ to give the title compound (5.2 g, 50.6%)as a solid. ¹H NMR (300 MHz, CDCl₃) δ 7.20-7.35 (mult, 5H), 3.86 (t,J=6.4 Hz, 2H), 3.66 (s, 2H), 2.50-2.57 (mult, 4H), 2.29 (s, 3H), 1.88(t, J=6.5 Hz, 2H), 1.65-1.84 (mult, 4H).

3d. 2-[1-Methyl-4(nitrosothio)-4-piperidyl]ethan-1-ol

The product of Example 3c (7.8 g, 29.38 mmol) was dissolved in THF (50mL) and cooled to −78° C. and liquid NH₃ (˜100 mL) was added. Smallpieces of metallic sodium (2 g) were added until the blue colorpersisted for 10 minutes. Solid NH₄Cl (˜5 g) was added to discharge thecolor and the cold bath was removed and ammonia was evaporated (12hours). Ether (100 mL) was added to the pale yellow solid and HCl inEt₂O (10 mL) was added until the solution became acidic. The mixture wasleft in a freezer for 30 min. The solid which formed was removed byfiltration and washed with Et₂O (50 mL). The residue was triturated withMeOH (100 mL) and undissolved solid was removed by filtration. Thesolvent was concentrated to 25 mL and concentrated HCl (2 mL) was added.90% t-BuONO (3.1 mL, 23.7 mmol) was added via syringe. The resultingolive green solution was stirred at room temperature for 20 minutes andthen poured onto crushed ice (5 g). 10% Na₂CO₃ (10 mL) was added and themixture was extracted with EtOAc (3×50 mL). The combined organics weredried over Na₂SO₄ and concentrated to give the title compound (3.6 g,60%) as a green oil. ¹H NMR (300 MHz, CDCl₃) δ 3.88 (t, J=6.9 Hz, 2H),2.25-2.95 (mult, 13H), 2.30 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 62.5,58.5, 57.8, 51.5, 46.1, 36.4.

3e. 4-[5-(Methyl)-3-phenylisoxazol-4-yl]benzenesulfonamide

This compound was synthesized as described in patent application WO96/25405, Example 1, the disclosure of which is incorporated byreference herein in its entirety. mp 170° C. ¹H NMR (300 MHz, CD₃CN) δ7.90 (d, J=8.4 Hz, 2H), 7.39-7.49 (mult, 7H), 5.48 (s, 2H), 2.50 (s, 2H); mass spectrum (API-TIS), m/z 315 (MH⁺).

3f. 2-[1-Methyl-4-(nitrosothio)-4-piperidyl]ethyl3-(N-{[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl}carbamoyl)propanoate

To a stirred solution of the product of Example 3d (0.21 g, 1.03 mmol),the product of Example 3e (0.43 g, 1.03 mmol), and4-(dimethylamino)pyridine (DMAP, 0.05 g) in CH₂Cl₂ (10 mL) was addedsolid DCC (0.34 g, 164 mmol). The solution was stirred for 24 hours atroom temperature. The precipitate which formed was removed by filtrationand the filtrate was concentrated under reduced pressure. The crudeproduct was chromatographed on silica gel eluting with 1:1 EtOAc:Hexfollowed by 1:9 MeOH:CH₂Cl₂. This gave the title compound (178 mg, 29%)as a green foam. ¹H-NMR (300 MHz, CDCl₃) δ 7.94 (d, J=8.2 Hz, 2H),7.22-7.39 (mult, 7H), 4.47-4.57 (mult, 2H), 3.56-3.60 (mult, 2H),3.15-3.25 (mult, 2H), 2.45-2.90 (mult, 10H), 2.42 (s, 6H); ¹³C-NMR (75MHz, CDCl₃) δ 178.5, 173.4, 167.1, 161.0, 143.0, 133.5, 129.7, 129.5,128.6, 128.5, 128.4, 126.7, 114.9, 60.0, 56.2, 51.7, 45.5, 41.0, 33.9,31.8, 30.3, 11.6; mass spectrum (API-TIS), m/z 601 (MH⁺).

3g. 2-[1-Methyl-4(nitrosothio)-4-piperidyl]ethyl3-(N-{[4-(5-methyl-3-phenylisoxazolyl-4-yl)phenyl]sulfonyl}carbamoyl)propanoate Citrate Salt

Citric acid (65 mg, 0.34 mmol) in MeOH (0.2 mL) was added to the productof Example 3f (170 mg, 0.28 mmol) dissolved in EtOAc (0.8 mL) and MeOH(0.4 mL). The green solution was left to crystallize at −20° C. for 48hours. The solvent was decanted and the solid was dried under reducedpressure for 16 hours to give the title compound (124 mg, 55%) as shiny,olive green crystals. mp 82-84° C. (decom). ¹H-NMR (300 MHz, CDCl₃) δ8.16 (d, J=8.4 Hz, 2H), 7.52-7.60 (mult, 7H), 4.43 (t, J=6.4 Hz, 2H),3.15-3.25 (mult, 2H), 2.50-2.99 (mult, 22H); mass spectrum (API-TIS),m/z 601 (MH⁺).

Example 4(2-{1-[(4-Chlorophenyl)methyl]-5-methoxy-2-methylindol-3-yl}ethyl)nitrooxy4a.2-{1-[(4-Chlorophenyl)methyl]-5-methoxy-2-methylindol-3-yl}ethan-1-ol

A solution of indomethacin (10 g, 28 mmol) in THF (90 mL) was immersedin an ice bath to maintain an internal temperature of 10-15° C. To thissolution was added BF₃-Et₂O (30 mL, 230 mmol) over 5 min, resulting inthe formation of a precipitate. Sodium borohydride (4.2 g, 110 mmol) wasadded portionwise over 10 min resulting in vigorous effervescence. Aftergas evolution subsided the flask was stoppered and allowed to warm toroom temperature. After 1 hour the pressure was vented through a needle.The heterogeneous mixture was stirred for 6 hours. The mixture wascooled in an ice bath and was quenched by adding saturated NaHCO₃. Tobreak the resultant emulsion the mixture was made acidic with 1N HCl andextracted with a 3:1 mixture of Et₂O:Hexane (270 mL). The organic layerwas washed with brine, dried over Na₂SO₄, and evaporated. The residuewas taken up in a 3:1 mixture of hot Hex:EtOAc (80 mL). Upon cooling toroom temperature, crystals began to form. Crystallization was completedby cooling to −20° C. The solid was removed by filtration, washed withcold 3:1 Hex:EtOAc (2×25), Hexane (1×25) and dried in vacuo. This gavethe title compound (4.5 g, 49%) as a white solid. mp 113-115° C. ¹H-NMR(300 MHz, CDCl₃) δ 7.24 (d, J=8.4 Hz, 2H), 7.06 (d, J=9.1 Hz, 1H), 7.03(d, J=3.5 Hz, 1H), 6.87 (d, J=8.3 Hz, 2H), 6.78 (dd, J=2.4 and 8.7 Hz,1H), 5.23 (s, 2H), 3.86 (s, 3H), 3.84 (t, J=6.5 Hz, 2H), 2.99 (t, J=6.5Hz, 2H), 2.29 (s, 3H); mass spectrum (API-TIS) m/z 330 (MH⁺). Anal calcdfor C₁₉H₂₀ClNO₂: C, 69.19; H, 6.11; N, 4.25; Cl, 10.75. Found: C, 68.98;H, 6.30; N, 4.08; Cl, 10.60.

4b. 3-(2-Bromoethyl)-1-[(4-chlorophenyl)methyl]-5-methoxy-2-methylindole

To the product of Example 4a (160 mg, 0.5 mmol) in toluene (1 mL) wasadded PBr₃ (17 μL, 0.18 mmol). The reaction mixture was heated to 100°C. for 10 min then cooled to room temperature. The mixture waspartitioned between EtOAc and 1N HCl. The aqueous layer was extractedwith EtOAc (1×10). The combined organic layers were washed with H₂O(1×10), brine (2×10), dried over Na₂SO₄, and evaporated. This gave thetitle compound (170 mg, 87%) which solidified on standing. This materialwas used in the next reaction without further purification. ¹H-NMR (300MHz, CDCl₃) δ 7.24 (d, J=8.4 Hz, 2H), 7.06 (d, J=9.1 Hz, 1H), 6.99 (d,J=2.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.78 (dd, J=2.4 and 8.8 Hz, 1H),5.23 (s, 2H), 3.87 (s, 3H), 3.56 (t, J=7.5 Hz, 2H), 3.28 (t, J=7.5 Hz,2H), 2.29 (s, 3H).

4c.(2-{1-[(4-Chlorophenyl)methyl]-5-methoxy-2-methylindol-3-yl}ethyl)nitrooxy

The product of Example 4b (170 mg, 0.43 mmol) was dissolved in CH₃CN (6mL). Addition of AgNO₃ (85 mg, 0.5 mmol) caused immediate formation of aprecipitate. After 20 min, the reaction mixture was filtered throughCelite and concentrated. The residue was purified by chromatography onsilica gel eluting with 5:1 Hex:EtOAc. This gave the title compound (90mg, 56%) as a white crystalline solid. mp 94-95° C. ¹H-NMR (300 MHz,CDCl₃) δ 7.23 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.9 Hz, 1H), 6.99 (d, J=2.4Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.79 (dd, J=2.4 and 8.4 Hz, 1H), 5.23(s, 2H), 4.60 (t, J=7.2 Hz, 2H), 3.87 (s, 3H), 3.14 (t, J=7.3 Hz, 2H),2.28 (s, 3H); mass spectrum (API-TIS): m/z 375 (MH⁺). Anal calcd forC₁₉H₁₉ClN₂O₄: C, 60.88; H, 5.11; N, 7.47; Cl, 9.46. Found: C, 60.89; H,5.23; N, 7.36; Cl, 9.58.

Example 51-[3-(4-Fluorophenyl)-7-(nitrooxymethyl)(3a-hydroimidazolo[1,2-a]pyridin-2-yl)]-4-(methylsulfonyl)benzene5a.1-[3-(4-Fluorophenyl)-7-(hydroxymethyl)(3a-hydroimidazolo[1,2-a]pyridin-2-yl)]-4(methylsulfonyl)benzene

This compound was prepared according to a procedure described in patentapplication WO 96/31509, (the disclosure of which is incorporated byreference herein in its entirety), Example 15.¹H-NMR (300 MHz, CDCl₃) δ7.80-7.87 (m, 5H), 7.40-7.46 (m, 2H), 7.20-7.33 (m, 3H), 6.82-6.86 (t,2H, J=7.0 Hz), 5.11 (s, 2H), 3.04 (s, 3H); mass spectrum (API-TIS) m/z397 (MH⁺).

5b.1-[3-(4-Fluorophenyl)-7-(nitrooxymethyl)(3a-hydroinidazolo[1,2-a]pyridin-2-yl)]-4(methylsulfonyl)benzene

A suspension of the product of Example 5a (210 mg, 0.52 mmol) was addedto an ice-cold mixture of acetic anhydride (393 μL, 4.16 mmol) andnitric acid (110 μL, 2.61 mmol). The resulting mixture was allowed towarm up to 10° C. and stirred for 1 hour. The mixture was then dilutedwith methylene chloride, washed with cold saturated sodium bicarbonatesolution and brine, dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was suspended in hexane/ethyl acetate (2:1)mixture and filtered to give 230 mg (99% yield) of the title compound asa yellow-orange solid. m.p. 145-147° C. ¹H-NMR (300 MHz, CDCl₃ ) δ8.07-8.12 (d, 1H, J=7.0 Hz), 7.82-7.56 (m, 4H), 7.48-7.56 (m, 2H),7.32-7.39 (m, 2H), 6.95-7.01 (t, 1H, J=7.0 Hz), 5.96 (s, 2H), 3.12 (s,3H).

Example 6 Ethyl6-chloro-8-[(nitrooxy)methyl]-2-(trifluoromethyl)-2H-chromene-3carboxylate 6a. Ethyl6-chloro-8-formyl-2-(trifluoromethyl)-2H-chromene-3 carboxylate

This compound was synthesized as described in patent application WO98/47890, (the disclosure of which is incorporated by reference hereinin its entirety), Example 76. ¹H-NMR (300 MHz, CDCl₃) δ 10.39 (s, 1H),7.79 (s, 1H), 7.69 (s, 1H), 7.40 (s, 1H), 5.86 (q, J=6.6 Hz, 1H),4.31-4.44 (mult, 2H), 1.37 (t, J=7.1 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ186.3, 163.0, 153.5, 134.4, 134.1, 130.1, 128.4, 125.0, 124.8, 121.8,121.0, 119.2, 71.1 (q, J_(C-F)=134 Hz), 62.0, 14.1.

6b. Ethyl 6-chloro-8-(hydroxymethyl)-2-(trifluoromethyl)-2H-chromene-3carboxylate

Na(OAc)₃BH (2.4 g, 11.2 mmol) was added to a stirred solution of theproduct of Example 6a (1.5 g, 4.5 mmol) in CH₂Cl₂ (50 mL) and theresulting solution was stirred at room temperature for 3 days. Thesolution was poured into water (100 mL), the CH₂Cl₂ layer was separatedand the aqueous layer was extracted with CH₂Cl₂ (2×25 mL). The combinedorganic layers were dried over Na₂SO₄. The solvent was evaporated underreduced pressure and the crude material was chromatographed on silicagel eluting with EtOAc:Hexane (1:5) to give the title compound (1.2 g,79%) as a white solid. mp 98-100° C. ¹H-NMR (300 MHz, CDCl₃) 7.66 (s,1H), 7.41 (d, J=2.3 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 5.76 (q, J=6.7 Hz,1H), 4.71 (d, J=5.5 Hz, 2H), 4.26-4.70 (mult, 2H) , 2.06-2.10 (br mult,1H), 1.15-1.21 (mult, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 163.4,146.7,135.7,131.2, 130.3, 127.7, 127.6, 121.3, 120.1, 118.0, 70.6 (q, J_(C-F)=133Hz), 61.7,59.6, 14.1; mass spectrum (API-TIS) m/z 354 (M+NH₄ ⁺). Anal.Calcd for C₁₄H₁₂ClF₃O₄: C, 49.94; H, 3.59; F, 16.93; Cl, 10.53. Found:C, 49.83; H, 3.52; F, 17.10; Cl, 10.77.

6c. Ethyl6-chloro-8-[(nitrooxy)methyl]-2-(trifluoromethyl)-2H-chromene-3carboxylate

Fuming HNO₃ (340 μL, 3.6 mmol) was added to a stirred solution of aceticanhydride (1.12 mL, 11.8 mmol) in EtOAc (10 mL) at 0° C. via syringe.The mixture was allowed to stir for 5 min at 0° C. The product ofExample 6b (0.5 g, 1.49 mmol) in EtOAc (10 mL) was then added andstirred for 15 min at 0° C. The reaction mixture was poured into icecold saturated NaHCO₃ (25 mL) and shaken well. The organic layer wasseparated and dried over Na₂SO₄. The solvent was evaporated underreduced pressure to afford a viscous oil which was dissolved in hexane(15 mL). The resulting solution was left in a freezer at −20° C. for 12hours to give the title compound (0.44 g, 77%). mp 53° C. ¹H-NMR (300MHz, CDCl₃) δ 7.65 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.25 (d, J=2.4 Hz,1H), 5.78 (q, J=6.6 Hz, 1H), 5.46 (s, 2H), 4.28-4.38 (mult, 3H), 1.35(t, J=7.1 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 163.0, 150.0, 135.0, 133.0,130.0, 127.6, 125.0, 121.8, 121.1, 120.8, 118.8, 71.3 (q, J_(C-F)=133Hz), 68.0, 61.8, 14; mass spectrum (API-TIS) m/z 399 (M+NH₄ ⁺). Anal.Calcd for C₁₄H₁₁ClF₃O₆: C, 44.06; H, 2.90; F, 14.93; Cl, 9.29; N, 3.67.Found: C, 44.00; H, 2.85; F, 14.83; Cl, 9.14; N, 3.57.

Example 72-{1-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-(2-methyl-2-(nitrosothio)propyl)acetamide7a.2-11-[(4Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-(2-methyl-2-sulfanylpropyl)acetamide

A solution of indomethacin (3.6 g, 10 mmol) and Et₃N (1.5 mL, 11 mmol)in THF (50 mL) was cooled to 0° C. i-Butyl chloroformate (1.5 mL, 11mmol) was added dropwise and the reaction was allowed to stir for 20min. To the resulting solution was added a slurry of1-amino-2-methyl-2-propanethio.HCl (1.4 g, 10 mmol) and Et₃N (1.5 mL, 11mmol) in DMF (20 mL). The reaction mixture was kept cold for 2 hours,warmed to room temperature and stirred for 1 hour. The mixture waspartitioned between Et₂O and dilute HCl. The organic layer was separatedand washed with saturated NaHCO₃, brine, filtered and dried over Na₂SO₄.Evaporation of the solvent gave a residue which was recrystallized fromEtOAc to give the title compound (1.1 g, 25%) as a white solid. mp177-178° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.67 (d, J=8.5 Hz 2H), 7.48 (d,J=8.4 Hz, 2H), 6.92 (d, J=2.3 Hz, 1H), 6.91 (d, J=9.0 Hz, 1H), 6.71 (dd,J=2.5 and 9.1 Hz, 1H), 6.10 (br t, J=6.3 Hz, 1H), 3.83 (s, 3H), 3.69 (s,2H), 3.27 (d, J=6.3 Hz, 2H), 2.42 (s, 3H), 1.36 (s, 1H), 1.26 (s, 6H);mass spectrum (API-TIS) m/z 445(447) MH⁺ (1-Cl).

7b.2-{1-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-(2-methyl-2-(nitrosothio)propyl)acetamide

The product of Example 7a (25 mg, 0.056 mmol) was dissolved in CH₂Cl₂ (1mL) and cooled to 0° C. A solution of t-BuONO (7.5 μL, 0.056 mmol) inCH₂Cl₂ was added dropwise. The reaction mixture was allowed to warm toroom temperature with stirring for 30 min. Evaporation of the solventgave the title compound (25 mg, 100%) as a green crystalline solid. mp122-125° C. dec. ¹H-NMR (300 MHz, CDCl₃) δ 7.64 (d, J=8.5 Hz, 2H), 7.51(d, J=8.4 Hz, 2H), 6.84 (d, J=9.1 Hz, 1H), 6.82 (d, J=2.5 Hz, 1H), 6.78(dd, J=2.5 and 9.1 Hz, 1H), 5.96 (br t, J=6.4 Hz, 1H), 3.97 (d, J=6.4Hz, 2H), 3.79 (s, 3H), 3.67 (s, 2H), 2.32 (s, 3H), 1.78 (s, 6H); massspectrum (API-TIS) m/z 491(493) M+NH⁺ (1-Cl).

Example 8 Ethyl(2Z)-3-(4-chlorophenyl)-3-14-(methylsulfonyl)phenyl]-2-[2-(nitrooxy)ethyl]prop-2-enoate8a. Ethyl(2Z)-3-(4-chlorophenyl)-2-(2-hydroxyethyl)-3-[4-(methylsulfonyl)phenyl]prop-2-enoate

This compound was synthesized as described in U.S. Pat. No. 5,807,873,(the disclosure of which is incorporated by reference herein in itsentirety), Example 64. mp 126° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.93 (dd,J=1.75 and 8.3 Hz, 2H), 7.46 (dd, J=1.78 and 6.7 Hz, 2H), 7.25-7.30(mult, 2H), 7.04-7.09 (mult, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.76 (t, J=6.2Hz, 2H), 3.09 (s, 3H), 2.62 (t, J=6.1 Hz, 2H), 0.97 (t, J=7.1 Hz, 3H);¹³C NMR (75 MHz, CDCl₃) δ 170.2, 145.6, 144.6, 140.0, 139.5, 134.2,132.7, 130.3, 129.9, 128.5, 127.6, 61.3, 61.1, 44.4, 35.0, 13.6; massspectrum (API-TIS) m/z 409 (MH⁺), 426 (MNH₄ ⁺). Anal. Calcd forC₂₀H₂₁ClO₅S: C, 58.75; H, 5.18; Cl, 8.67; S, 7.84. Found: C, 58.64; H,5.02; Cl, 8.80; S. 7.79.

8b. Ethyl(2Z)-3-(4-chlorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-[2-(nitrooxy)ethyl]prop-2-enoate

A suspension of the product of Example 8a (2.02 g, 4.95 mmol) in CHCl₃(20 mL) was added dropwise to a mixture of acetic anhydride (3.71 mL,4.04 g, 39.6 mmol) and 90% fuming nitric acid (1.03 mL, 1.56 g, 24.8mmol) at −12° C. The resultant solution was stirred at −12° C. for 1hour. CH₂Cl₂ (30 mL) was added, washed with ice cold saturated NaHCO₃,dried over Na₂SO₄ and filtered. Evaporation of the solvent gave aresidue that was recrystallized from 1:2 Hexane:CH₂Cl₂ to give the titlecompound (1.82 g, 82%) as a white solid. mp 127-128° C. ¹H-NMR (300 MHz,CDCl₃) δ 7.97 (d, J=8.3 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 7.27-7.31(mult, 2H), 7.03-7.08 (mult, 2H), 4.59 (t, J=6.4 Hz, 2H), 4.02 (q, J=7.1Hz, 2H), 3.09 (s, 3H), 2.76 (t, J=6.4 Hz, 2H), 0.98 (t, J=7.1 Hz, 3H);¹³C NMR (75 MHz, CDCl₃) δ 168.8, 147.6, 145.3, 140.5, 139.2, 134.6,129.9, 129.8, 129.4, 128.7, 128.0, 70.8, 61.4, 44.5, 29.9, 13.6; massspectrum (API-TIS) m/z 471 (MNH₄ ⁺). Anal. Calcd for C₂₀H₂₀ClNO₇S: C,52.92; H, 4.44; N, 3.09; Cl, 7.81; S, 7.06. Found: C, 52.91; H, 4.35; N,2.93; Cl, 7.89, S, 7.20.

Example 9(2Z)-3-(4-Chlorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-[2-(nitrooxy)ethyl]prop-2-enoicacid 9a.(2Z)-3-(4-Chlorophenyl)-2-(2-hydroxyethyl)-3-[4-(methylsulfonyl)phenyl]prop-2-enoicacid

NaOH (6.4 mL of 1.5 N, 0.38 g, 9.6 mmol) was added dropwise to asolution of the product of Example 8a (3.62 g, 8.87 mmol) in ETOH (80mL) at 0° C. The resultant pale yellow solution was stirred at roomtemperature for 2 hours. The residue, after evaporation of the solvent,was dissolved in water and washed with EtOAc. Crushed ice was added tothe aqueous layer which was then acidified with 10% HCl to ˜pH=4 andextracted with EtOAc. The organic layer was dried over Na₂SO₄ andfiltered. Evaporation of the solvent gave a residue that wasrecrystallized from EtOAc:Hex:CH₂Cl₂ to give the title compound (2.79 g,82%) as a white solid. mp 144-145° C. ¹H-NMR (300 MHz, CDCl₃/MeOH-d₄) δ7.98 (d, J=7.1 Hz, 2H), 7.53 (d, J=7.0 Hz, 2H), 7.29-7.32 (mult, 2H),7.16-7.19 (mult, 2H), 3.71 (t, J=6.9 Hz, 2H), 3.15 (s, 3H), 2.56 (t,J=6.8 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 173.1, 147.4, 145.1, 141.4,141.2, 134.9, 134.3, 131.4, 131.3, 129.4, 128.7, 61.3, 61.3, 44.3, 36.3;mass spectrum (API-TIS) m/z 363 (M-H₂O), 381 (MH⁺), 398 (MNH₄ ⁺). Anal.Calcd for C₁₈H₁₇ClO₅S: C, 56.77; H, 4.50; Cl, 9.31; S, 8.42. Found: C,56.64; H, 4.44; Cl, 9.40; S, 8.18.

9b.(2Z)-3-(4-Chlorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-[2-(nitrooxy)ethyl]prop-2-enoic acid

A suspension of the product of Example 9a (1.37 g, 3.66 mmol) in CHCl₃(54 mL) was added dropwise to a mixture of acetic anhydride (2.72 mL,2.94 g, 28.8 mmol) and 90% fuming nitric acid (0.76 mL, 1.14 g, 18.0mmol) at −12° C. The resultant solution was stirred at −12° C. for 30min. CH₂Cl₂ (25 mL) was added, washed with water, dried over Na₂SO₄ andfiltered. Evaporation of the solvent gave a residue that wasrecrystallized from EtOAc:Hexane:CH₂Cl₂ to give the title compound (0.9g, 59%) as a white solid. mp 143-144° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.98(d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.27-7.32 (mult, 2H),7.07-7.11 (mult, 2H), 4.61 (t, J=6.3 Hz, 2H), 3.10 (s, 3H), 2.78 (t,J=6.3 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 172.8, 150.9, 145.4, 140.7,138.7, 135.1, 129.8, 129.7, 129.0, 128.1, 127.7, 70.8, 44.5, 30.0; massspectrum (API-TIS) m/z 443 (MNH₄ ⁺). Anal. Calcd for C₁₈H₁₆ClNO₇S: C,50.77; H, 3.79; N, 3.29; Cl, 8.33; S, 7.53. Found: C, 50.87; H, 3.67; N,3.13; Cl, 8.26, S, 7.43.

Example 10 (2Z)-3-(4-Chlorophenyl)-2-(2-hydroxyethyl)-N-[2-methyl-2(nitrosothio)propyl]-3-[4-(methylsulfonyl)phenyl]prop-2-enamide 10a.(2Z)-3-(4-Chlorophenyl)-N-(2-methyl-2-sulfanylpropyl)-3-[4-(methylsulfonyl)phenyl]-2-[2-(1,1,2,2,-tetramethyl-1-silapropoxy)ethyl]prop-2-enamide

To a solution of the product of Example 9a (0.5 g, 1.32 mmol) andimidazole (0.18 g, 2.63 mmol) in dry THF (10 mL) was added a solution oft-butyldimethyl-chlorosilane (0.4 g, 2.63 mmol) in dry THF (10 mL)dropwise at room temperature. The resulting white suspension was stirredat room temperature for 16 hours. The reaction mixture was partitionedbetween EtOAc and saturated NaHCO₃. The organic layer was separated,washed with 10% HCl, dried over Na₂SO₄, filtered and concentrated invacuo to give 1:1 mono:disilylated product as a white foam which wasused in the next step without further purification. Mass spectrum(API-TIS) m/z 495 and 609 (MH⁺). The entire white foam was dissolved inTHF (10 mL). Bis(2-oxo-3oxazolidinyl)phosphonic chloride (0.70 g, 1.58mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.32 mmol) were added atroom temperature. After 5 min, 1-amino-2-methyl-2-propanethiol (0.15 g,1.41 mmol) in THF (2 mL) was added dropwise. The resulting pale yellowsolution was stirred at room temperature for 2.5 hours. Evaporation ofthe solvent gave a residue that was chromatographed on silica geleluting with 1:1 EtOAc:Hexane to give the title compound (0.28 g, 37%)as a white foam. ¹H-NMR (300 MHz, CDCl₃) δ 7.90 (d, J=8.3 Hz, 2H), 7.56(d, J=8.3 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.15 (d, J=6.7 Hz, 2H), 5.91(t, J=6.2 Hz, 1H), 3.77 (t, J=5.9 Hz, 2H), 3.15 (d, J=6.2 Hz, 2H), 3.09(s, 3H), 2.64 (t, J=5.9 Hz, 2H), 1.28 (s, 1H), 1.11 (s, 6H), 0.96 (s,9H), 0.09 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 170.2, 145.9, 140.2, 139.8,139.4, 137.9, 134.4, 130.9, 130.6, 129.1, 127.4, 60.6, 60.4, 53.5, 52.7,44.6, 44.5, 35.0, 29.9, 26.1, 21.1, 18.4, 14.3, −5.2; mass spectrum(API-TIS) m/z 582 (MH⁺). Anal. Calcd for C₂₈H₄₀ClNO₄S₂Si: C, 57.76; H,6.92; N, 2.41. Found: C, 57.79; H, 6.67; N, 2.30.

10b.(2Z)-3-(4-Chlorophenyl)-2-(2-hydroxyethyl)-N-(2-methyl-2-sulfanylpropyl)-3-[4-(methylsulfonyl)phenyl]prop-2-enamide

To a solution of the product of Example 10a (225 mg, 0.39 mmol) in THF(13 mL) was added dropwise trifluoroacetic acid (129 μL, 1.67 mmol) at0° C. To this was added tetrabutylammonium fluoride (385 μL of 1Msolution in THF, 0.39 mmol) dropwise. The resultant solution wasgradually warmed to room temperature and stirred for 25 hours. Thereaction mixture was partitioned between EtOAc (50 mL) and ice cold 1%HCl. The organic layer was separated, dried over Na₂SO₄ and filtered.The solvent was evaporated and the residue was chromatographed on silicagel eluting with 5% MeOH:CH₂Cl₂ to give the title compound (175 mg, 97%)as a white foam. mp 62-64° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.93 (d, J=8.2Hz, 2H), 7.47 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.5 Hz, 2H), 7.16 (d, J=8.4Hz, 2H), 6.05 (t, J=6.1 Hz, 1H), 3.72 (t, J=5.7 Hz, 2H), 3.14 (d, J=6.1Hz, 2H), 3.09 (s, 3H), 2.59 (t, J=5.7 Hz, 2H), 1.36 (s, 1H), 1.16 (s,6H); ¹³C NMR (75 MHz, CDCl₃) δ 171.1, 145.8, 141.1, 140.0, 138.8, 137.3,134.7, 130.5, 130.4, 129.2, 127.8, 61.0, 52.9, 44.7, 44.6, 34.9, 30.0;mass spectrum (API-TIS) m/z 468 (MH⁺).

10c.(2Z)-3-(4-Chlorophenyl)-2-(2-hydroxyethyl)-N-(2-methyl-2-(nitrosothio)propyl)-3-[4-(methylsulfonyl)phenyl]prop-2-enamide

To a solution of t-butyl nitrite (0.2 mL of 90% solution, 158 mg, 1.53mmol) in 1:1 MeOH:CH₂Cl₂ (1.2 mL) was added dropwise a solution of theproduct of Example 10b (156 mg, 0.33 mmol) in 1:1 MeOH:CH₂Cl₂ (2 mL) at0° C. The resultant solution was stirred at 0° C. in the dark for 30min. Additional t-butyl nitrite (0.15 mL of 90% solution, 118 mg, 1.15mmol) was added and the resultant green solution was stirred at 0° C.for a further 30 min and then at room temperature for 20 min. Thevolatiles were removed in vacuo and the residue was chromatographed onsilica gel eluting with 1:1 EtOAc:CH₂Cl₂ to give the title compound (96mg, 58%) as a green solid. mp 150-153° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.90(d, J=8.3 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.24 (dd, J=1.9 and 6.6 Hz,2H), 7.09-7.12 (mult, 2H), 6.40 (br t, J=6.3 Hz, 1H), 3.86 (d, J=6.3 Hz,2H), 3.66 (t, J=5.9 Hz, 2H), 3.09 (s, 3H), 2.54 (t, J=5.8 Hz, 2H), 1.67(s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 171.4, 145.8, 141.2, 139.8, 138.8,136.9, 134.5, 130.5, 130.3, 129.0, 127.6, 60.5, 56.5, 44.5, 34.7, 26.8;mass spectrum (API-TIS) m/z 467 (M-NO), 497 (MH⁺).

Example 111-[5-methyl-1-(2-methyl-2-(nitrosothio)propyl)pyrrol-2-yl]-4-(methylsulfonyl)benzene11a. 1-(4-Methylthiophenyl)pentane-1,4-dione

4-(Methylthio)benzaldehyde (20 mL, 150 mmol),3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (7 g, 30 mmol),methyl vinyl ketone (15 mL, 180 mmol), and Et₃N (21 mL, 150 mmol) wereplaced in a flask and immersed in an oil bath at 80° C. The initialpurple colored solution became orange over 30 min. The solution wascooled to room temperature, EtOAc (30 mL) was added to precipitate thethiazolium salt which was removed by filtration. The filter cake waswashed with hot EtOAc (2×30 mL). The combined mother liquor and washeswere concentrated to give 43 g of residue. The residue was taken up inhot 1:1 Hexane:EtOAc (100 mL), which upon cooling deposited a solid.This solid was isolated on a glass frit and washed with hot 4:1Hexane:EtOAc (50 mL). From this hot wash was deposited the titlecompound (16.4 g, 49%) as a tan solid. mp 72-73° C. ¹H-NMR (300 MHz,CDCl₃) δ 7.88 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 3.22 (t, J=6.5Hz, 2H), 2.87 (t, J=6.2 Hz, 2H), 2.51 (s, 3H), 2.24 (s, 3H); massspectrum (API-TIS) m/z 223 (MH⁺). Anal. Calcd. for C₁₂H₁₄O₂S: C, 64.84;H, 6.35; S, 14.42. Found C, 64.68; H, 6.19; S, 14.24.

11b. 1-[4-(Methylsulphonyl)phenyl]pentane-1,4-dione

The product of Example 11a (16.4 g, 74 mmol) was dissolved in CH₂Cl₂(300 mL) and cooled to 0° C. Solid 70% m-chloroperbenzoic acid (37 g,150 mmol) was added portionwise over 5 min. After complete addition thecold bath was removed and the reaction mixture was allowed to warm toroom temperature with stirring for 3 hours. The precipitate that hadformed was removed by filtration and washed with CH₂ Cl₂ (2×50 mL). Thecombined organic filtrates were washed with 1M Na₂CO₃, dried overNa₂SO₄, and concentrated. The residue was partitioned between EtOAc (200mL) and 1M Na₂CO₃ (50 mL). The solid was kept with the aqueous layer andthe mixture was extracted with EtOAc (50 mL). The aqueous layer wasfiltered to give the title compound (8.9 g) after drying in vacuo. Thecombined organic layers were washed with water, brine, dried overNa₂SO₄, and concentrated to give additional title compound (6.5 g).Overall yield of the title compound was 15.4 g, 82%. mp 132-133° C.¹H-NMR (300 MHz, CDCl3) δ 8.15 (d, J=8.4 Hz, 2H), 8.05 (d, J=8.3 Hz,2H), 3.27 (t, 6.6 Hz, 2H), 3.07 (s, 3H), 2.93 (t, J=6.4 Hz, 2H), 2.26(s, 3H); mass spectrum (API-TS) m/z 255 (MH⁺). Anal. Calcd. forC₁₂H₁₄O₄S: C, 56.68; H, 5.55; S, 12.61. Found: C, 56.39; 5.40; S, 13.36.

11c.1-[5-Methyl-1-(2-methyl-2-sulfanylpropyl)pyrrol-2-yl]-4-(methylsulfonyl)benzene

The product of Example 1b (2 g, 7.9 mmol), NaOAc (1.3 g, 16 mmol), and1-amino-2-methyl-2-propanethiol.HCl (1.2 g, 8.7 mmol) were added to HOAc(15 mL) and heated to 80° C. for 3 hours. The reaction mixture wascooled to room temperature and the HOAc was removed at reduced pressure.The residue was partitioned between EtOAc (40 mL) and 1N Na₂CO₃ (15 mL).The organic layer was separated and washed with 1N Na₂CO₃, brine, thendried over Na₂SO₄ and concentrated. The residue was crystallized fromhot MeOH (5 mL) to gave the title compound (1.6 g, 63%) as an orange-tansolid. mp 124-126° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.93 (d, J=8.4 Hz, 2H),7.52 (d, J=8.4 Hz, 2H), 6.22 (d, J=3.6 Hz, 1H), 6.03 (d, J=3.6 Hz, 1H),4.24 (br, 2H), 3.08 (s, 3H), 2.41 (s, 3H), 1,55 (s, 1H), 1.04 (s, 6H);mass spectrum (API-TIS) m/z 324 (MH+).

11d.1-[5-Methyl-1-(2-methyl-2-(nitrosothio)propyl)pyrrol-2-yl]-4-(methylsulfonyl)benzene

The product of Example 11c (100 mg, 0.31 mmol) was dissolved in CH₂Cl₂and cooled to 0° C. A solution of t-BuONO (40 mL, 31 mmol) in CH₂Cl₂(1mL) was added dropwise. After complete addition the reaction mixture waswarmed to room temperature and allowed to stir 1 hour. The solvent wasevaporated and the residue was chromatographed on silica gel elutingwith 2:1 Hexane:EtOAc. This gave a 1:3 mixture of starting material anddesired product (67 mg, 61%). A small fraction of this mixture wasreacted with t-BuONO to give the title compound as a dark foam. ¹H-NMR(300 MHz, CDCl₃) δ 7.89 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 6.22(d, J=3.6 Hz, 1H), 6.05 (d, J=3.5 Hz, 1H), 4.60-5.00 (br, 2H), 3.15 (s,3H), 2.39 (s, 3H), 1.6-2.0 (br s, 6H); mass spectrum (API-TIS) m/z 353(MH+).

Example 12 3-{4-[1-Methyl-1-(nitrosothio)ethyl]-2-oxo-1,3-oxazolidin-3yl}propyl (2Z)-4-acetyloxy-2-(4-fluorophenyl)-3-[4 (methylsulfonyl)phenyl]but-2-enoate 12a.3-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-5-hydrofuran-2-one

This compound was synthesized as described in patent EP 0 788 476 B1,(the disclosure of which is incorporated by reference herein in itsentirety), lactone 11. mp 163° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.94 (d,J=8.6 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H), 7.38-7.43 (mult, 2H), 7.06-7.27(mult, 2H), 5.18 (s, 2H), 3.08 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.5,165.0, 161.7, 153.7, 142.2, 136.3, 131.4, 131.3, 128.6, 128.3, 128.0,125.3, 125.2, 116.4, 116.1,70.5,44.4; mass spectrum (API-TIS) m/z 333(MH⁺), 350 (MNH₄ ⁺). Anal. Calcd for C₁₇H₁₃FO₄S: C, 61.44; H, 3.94; F,5.72; S, 9.65. Found: C, 61.24; H, 3.89; F, 5.70; S, 9.52.

12b.1-[(1Z)-2-(4-Fluorophenyl)-3-hydroxy-1-(hydroxymethyl)prop-1-enyl]-4-(methylsulfonyl)benzene

A solution of diisobutylaluminium hydride (70.2 mL, 1M solution in THF,9.98 g, 70.2 mmol) was added dropwise to a solution of the product ofExample 12a (4.68 g, 14.1 mmol) in THF (190 mL) at 0° C. After stirringfor 30 min at 0° C. and then 1 hour at room temperature, the mixture wascooled to 0° C. Additional DIBAL (30 mL, 1M solution in THF, 4.27 g, 30mmol) was added dropwise and stirred for 1 hour at room temperature.This reaction mixture was poured into a solution of 1M sodium potassiumtartrate (200 mL) containing MeOH (50 mL). The aqueous mixture wasextracted with EtOAc. The organic layer was dried over Na₂SO₄, andfiltered. The solvent was removed in vacuo to give the title compound(4.7 g, 99%) as a colorless oil. ¹H-NMR (300 MHz, MeOH-d₄) δ 7.73 (d,J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.07-7.12 (mult, 2H), 6.85-6.91(mult, 2H), 4.64 (s, 2H), 4.62 (s, 2H), 3.06 (s, 3H); mass spectrum(API-TIS) m/z 337 (MH⁺), 354 (MNH₄ ⁺).

12c.(2Z)-3-(4-Fluorophenyl)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]but-2-enylacetate

Acetic anhydride (1.33 mL, 1.4 g, 14.0 mmol) was added dropwise to asolution of the product of Example 12b (4.7 g, 14.0 mmol), DMAP (56 mg,0.46 mmol) and triethylamine (5.89 mL, 42.3 mmol) in CH₂Cl₂ (600 mL) atroom temperature. The mixture was stirred for 1 hour at roomtemperature, washed with water and dried over Na₂SO₄. The residue, afterevaporation of the solvent, was chromatographed on silica gel elutingwith 1:1 to 3:2 EtOAc:Hexane to give the title compound (1.31 g, 25%) asa colorless oil, followed by its regio-isomer,(2Z)-2-(4-fluorophenyl)-4-hydroxy-3-[4-(methylsulfonyl)phenyl]but-2-enylacetate (1.37 g, 26%) also as a colorless oil.(2Z)-3-(4-fluorophenyl)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]but-2-enylacetate: ¹H-NMR (300 MHz, CDCl₃) δ 7.73 (d, J=8.4 Hz, 2H), 7.21 (d,J=8.5 Hz, 2H), 7.02-7.06 (mult, 2H), 6.80-6.86 (mult, 2H), 5.17 (s, 2H),4.63 (s, 2H), 3.01 (s, 3H), 1.99 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ171.4, 163.6, 160.4, 145.9, 143.6, 139.0, 135.6 (J_(19F-C)=3.4 Hz),134.3, 131.0, 130.9, 130.5, 127.3, 115.5, 115.2, 64.4, 63.4, 44.5, 21.0;mass spectrum (API-TIS) m/z 396 (MNH₄ ⁺).(2Z)-2-(4-Fluorophenyl)hydroxy-3-[4-(methylsulfonyl)phenyl]but-2-enylacetate: ¹H-NMR (300 MHz, CDCl₃) δ 7.70 (d, J=8.4 Hz, 2H), 7.30 (d, J=8AHz, 2H), 6.82-6.97 (mult, 4H), 5.16 (s, 2H), 4.61 (s, 2H), 2.99 (s, 3H),1.99 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 171.4, 163.4, 160.1, 146.8,141.0, 138.5, 136.7, 134.7 (J_(19F-C)=3.5 Hz), 131.0, 130.9, 130.1,126.9, 115.4, 115.1, 64.4, 62.8, 44.3, 20.8; mass spectrum (API-TIS) m/z396 (MNH₄ ⁺).

12d. (2Z)-3-(4-Fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-4oxobut-2-enylacetate

A mixture of the product of Example 12c (1.31 g, 3.47 mmol) and MnO₂(6.96 g, 80 mmol) in CH₂Cl₂ (175 mL) was stirred for 16 hours at roomtemperature and then filtered through a pad of Celite. The filtrate wasdried over Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (0.81 g, 62%) as yellow solid. ¹H-NMR (300 MHz, CDCl₃) δ 10.39(s, 1H), 7.79 (d, J=10.3 Hz, 2H), 7.31 (d, J=12.2 Hz, 2H), 6.88-6.91(mult, 4H), 5.45 (s, 2H), 3.02 (s, 3H), 2.00 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 190.9, 170.4, 164.1, 160.8, 149.6, 143.9, 141.3, 140.3, 132.4,132.3, 130.0, 129.9, 127.4, 115.7, 115.5, 62.1, 44.4, 20.7; massspectrum (API-TIS) m/z 394 (MNH₄+).

12e.(2Z)-4-Acetyloxy-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]but-2-enoicacid

To a solution of the product of Example 12d (0.81 g, 2.15 mmol) and2-methyl-2-butene (28.9 mL, 19.1 g, 273 mmol) in t-butanol (170 mL), wasadded a solution of NaClO₂ (4.87 g, 53.9 mmol) and NaH₂PO₄ (4.80 g, 40.1mmol) in water (10 mL). The mixture was stirred for 2 hours at roomtemperature. The residue, after evaporation of the solvent, wasdissolved in pH=7 buffer solution (250 mL) and extracted with EtOAc. Theaqueous layer was acidified with 10% HCl (˜pH=4-5) and extracted withEtOAc. The combined organic layers were dried over Na₂SO₄ and filtered.The residue after evaporation of the solvent was recrystallized fromEtOAc:Hex:CH₂Cl₂ to give the title compound (0.31 g, 37%) as a whitesolid. mp 187° C. ¹H-NMR (300 MHz, THF-d₈) δ 7.87 (d, J=8.1 Hz, 2H),7.47 (d, J=8.1 Hz, 2H), 7.21-7.25 (mult, 21H), 6.97-7.03 (mult, 2H),5.35 (mult, 2H), 3.08 (s, 3H), 1.97 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ170.8, 169.7, 165.2, 162.0, 144.9, 142.2, 141.9, 137.7, 133.9(J_(C-F)=3.5 Hz), 133.2, 133.1, 131.6, 128.4, 116.3, 116.0, 65.9, 44.5,20.8; mass spectrum (API-TIS) m/z 333 (M-HOAc), 410 (M+NH₄+). Anal.Calcd for C₁₉H₁₇FO₆S.½ H₂O: C, 56.85; H, 4.52; F, 4.73; S, 7.99. Found:C, 56.83; H, 4.45; F, 5.07; S, 7.94.

12f. 2-Amino-3-methyl-3-[(2,4,6-trimethoxyphenyl)methylthio]butanoicacid

A suspension of 2-amino-3-methyl-3-sulfanylbutanoic acid(D-penicillamine) (5.0 g, 34 mmol) in CH₂Cl₂ (150 mL) was cooled to 0°C. Trifluoroacetic acid (54 mL, 703 mmol) was added dropwise over aperiod of 5 min. Then 2,4,6-trimethoxy-benzyl alcohol (6.64 g, 34 mmol)in CH₂Cl₂ (137 mL) was added dropwise at 0° C. with stirring. Stirringwas continued for 1 hour at 0° C. and then for 2 hours at roomtemperature. The solvent was removed in vacuo and the residue was driedunder high vacuum for 3 hours. The crude red solid was recrystallizedfrom 1:1:1 CH₂Cl₂/MeOH/EtOAc to give the title compound (10.5 g, 95%) asa white solid. ¹H-NMR (300 MHz, CDCl₃) δ 6.10 (s, 2H), 3.84 (s, 6H),3.76 (s, 3H), 3.40-4.10 (m, 3H), 1.69 (s, 3H), 1.23 (s, 3H); massspectrum (API-TIS) m/z 330 (MH⁺).

12g. 2-Amino-3-methyl-3-[(2,4,6-trimethoxyphenyl)methylthio]butan-1-ol

To a stirred solution of the product of Example 12f (10.5 g, 32 mmol) inTHF (80 mL) was added dropwise lithium aluminum hydride (1 M in THF, 64mL, 64 mmol) at 0° C. under nitrogen. The resulting solution was stirredat 0° C. for 1 hour and then at room temperature for 2 hours. The excessreducing agent was destroyed by careful portionwise addition ofNa₂SO₄.10H₂O at 0° C. The granular white precipitate was filtered andwashed with 30% methanol in CH₂Cl₂. The combined filtrate was dried overNa₂SO₄, filtered and evaporated to give the title compound (7.6 g, 76%)as a yellow oil which was used for the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃) δ 6.10 (s, 2H), 3.85 (s, 6H), 3.81(s, 3H), 3.74 (s, 2H), 3.60-3.80 (mult, 2H), 3.37-3.43 (mult, 1H),2.93-2.98 (mult, 1H), 1.45 (s, 3H), 1.30 (s, 3H); mass spectrum(API-TIS) m/z 316 (MH⁺).

12h.4-11-Methyl-l-[(2,4,6-trimethoxyphenyl)methylthioethyl-l3oxazolidin-2-one

A mixture of K₂CO₃ (0.33 g, 2.4 mmol), diethylcarbonate (50 mL) and theproduct of Example 12g (7.6 g, 24 mmol) was heated at 100° C. for 24hours. Excess diethylcarbonate was evaporated and the resultant lightbrown slurry was cooled to room temperature, diluted with CH₂Cl₂ andfiltered to remove the K₂CO₃. The filtrate was evaporated and theresidue was chromatographed on silica gel eluting with 1:1 EtOAc:Hexaneto give the title compound 2.6 g (32%) as a viscous yellow oil. ¹H-NMR(300 MHz, CDCl₃) δ 6.13 (s, 2H), 6.07 (bs, 1H), 4.30-4.40 (mult, 1H),4.25-4.28 (mult, 1H), 4.03-4.08 (mult, 1H), 3.86 (s, 6H), 3.83 (s, 2H),3.81 (s, 3H), 1.32 (s, 3H), 1.27 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ160.7, 159.5, 158.7, 106.3, 90.9, 66.5, 59.5, 56.0, 55.5, 47.1, 23.8,22.3, 20.3; mass spectrum (API-TIS) m/z 342 (MH⁺), 359 (MNH₄ ⁺).

12i. 3-Bromo-1-(1,1,2,2-tetramethyl-1-silapropoxy)propane

t-Butyldimethylchlorosilane (17.4 g, 115 mmol) in dry THF (50 mL) wasadded dropwise to a solution of 1,3-bromopropanol (16 g, 115 mmol) andimidazole (7.85 g, 115 mmol) in dry THF (50 mL) at room temperature. Theresulting white suspension was stirred at room temperature for 16 hours.The reaction mixture was diluted with EtOAc (200 mL), washed with water,brine, dried over Na₂SO₄, filtered, and concentrated in vacuo at roomtemperature to give the title compound 28.5 g (98%) as a colorlessvolatile liquid. ¹H-NMR (300 MHz, CDCl₃) δ 3.74 (t, J=5.7 Hz, 2H), 3.52(t, J=6.5 Hz, 2H), 2.02-2.06 (mult, 2H), 0.90 (s, 9H), 0.07 (s, 6H); ¹³CNMR (75 MHz, CDCl₃) δ 60.6, 35.7, 30.8, 26.1, −5.2.

12j.4-{1-Methyl-1-[(2,4,6-trimethoxyphenyl)methylthio]ethyl}-3-[3-(1,1,2,2-tetramethyl-1-silapropoxy)propyl]-1,3-oxazolidin-2-one

NaH (0.84 g, 35.3 mmol) was added portionwise to a solution of theproduct of Example 12h (8.03 g, 23.5 mmol) in dry DMF (25 mL) undernitrogen at 0° C. The resulting suspension was stirred at 0° C. for 20min to give a brown red solution. The product of Example 12i (7.14 g,28.2 mmol) in DMF (7 mL) was added dropwise and stirred at roomtemperature for 16 hours and then the solvent was evaporated. Theresidue was treated with 1:1 EtOAc:water and the organic layer wasseparated. The aqueous layer was extracted with EtOAc and the combinedorganic phases were washed with water, dried over Na₂SO₄, and filtered.Evaporation of the solvent left a residue that was chromatographed onsilica gel eluting with 5% to 25% EtOAc:Hexane to give the titlecompound 6.2 g (51%) as a white foam. ¹H-NMR (300 MHz, CDCl₃) δ 6.11 (s,2H), 4.38-4.42 (mult, 1H), 4.05-4.11 (mult, 1H), 3.93-3.96 (mult, 1H),3.83 (s, 6H), 3.80 (s, 3H), 3.77 (s, 2H), 3.65 (t, J=6.1 Hz, 2H),3.58-3.71 (mult, 1H), 3.34-3.44 (mult, 1H), 1.66-1.96 (mult, 2H), 1.56(s, 3H), 1.24 (s, 3H), 0.89 (s, 9H), 0.04 (s, 6H); ¹³C NMR (75 MHz,CDCl₃) δ 160.7, 159.5, 158.7, 107.0, 90.8, 65.7, 61.7, 60.6, 55.9, 55.4,48.3, 42.6, 30.3, 26.8, 26.0, 22.2, 20.4, 18.4, −5.3; mass spectrum(API-TIS) m/z 514 (MH⁺). #

12k.3-(3-Hydroxypropyl)-4-(1-methyl-1-sulfanylethyl)-1,3-oxazolidin-2-one

The product of Example ¹²j (5.0 g, 9.75 mmol) was treated with water(4.0 mL), phenol (4.0 g), anisole (4.0 mL) and finally trifluoroaceticacid (49 mL). The resultant solution was stirred at room temperature for1 hour. The volatiles were evaporated to give a yellow oil. The crudeyellow oil was chromatographed on silica gel eluting with 1:1EtOAc:Hexane to 5% MeOH:CH₂Cl₂ to give the title compound 1.4 g (66%) asa pale yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 4.30-4.35 (mult, 2H),3.50-3.82 (mult, 5H), 2.80-2.95 (bs, 1H), 1.83-1.89 (mult, 2H), 1.78 (s,1H), 1.42 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 160.5, 65.8, 65.4, 59.2,47.2, 42.2, 30.1, 29.0, 28.0; mass spectrum (API-TIS) m/z 220 (MH⁺), 237(MNH₄ ⁺). Anal. Calcd for C₉H₁₇NO₃S: C, 49.29; H, 7.81; N, 6.39. Found:C, 48.99; H, 7.71; N, 6.04.

12l.3-(3-Hydroxypropyl)-4-[1-methyl-1-(nitrosothio)ethyl]-1,3-oxazolidin-2-one

To a solution of t-BuONO (1.67 mL of 90% solution, 1.32 g, 12.8 mmol) inCH₂Cl₂ (10 mL) was added dropwise a solution of the product of Example12k (1.4 g, 6.4 mmol) in CH₂Cl₂ (16 mL) at 0° C. The resulting greensolution was stirred at 0° C. for 1 hour and then at room temperaturefor 20 min in the dark. Evaporation of the solvent gave a residue thatwas chromatographed on silica gel eluting with 1:1 EtOAc:CH₂Cl₂ to 5%MeOH:CH₂Cl₂ to give the title compound 0.98 g (62%) as a green oil.¹H-NMR (300 MHz, CDCl₃) δ 4.61-4.66 (mult, 1H), 4.36-4.46 (mult, 2H),3.42-3.75 (mult, 4H), 2.30-2.45 (br s, 1H), 1.97 (s, 3H), 1.96 (s, 3H),1.74-1.80 (mult, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 160.2, 65.3, 63.3, 59.3,58.8, 42.3, 29.8, 25.4, 25.0; mass spectrum (API-TIS) m/z 219 (M-NO),249 (MH⁺), 266 (MNH₄ ⁺). Anal. Calcd for C₉H₁₆N₂O₄S: C, 43.54; H, 6.50;N, 11.28. Found: C, 43.61; H, 6.59; N, 10.99.

12m.3-{4-[1-Methyl-1-(nitrosothio)ethyl]-2-oxo-1,3-oxazolidin-3-yl}propyl(2Z)-4-acetyloxy-2-(4-flurophenyl)-3-[4-(methylsulfonyl)phenyl]but-2-enoate

Bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.14 g, 0.32 mmol) and4-(dimethylamino)pyridine(19.0 mg, 0.16 mmol) were added to a solutionof the product of Example 12l (100 mg, 0.40 mmol) and the product ofExample 12e (61 mg, 0.16 mmol) in THF (2 mL) at 0° C. The resultingsolution was stirred at 0° C. for 1 hour and then at room temperaturefor 20 hours. Evaporation of the solvent gave a residue that waschromatographed on silica gel eluting with 1:1 EtOAc:CH₂Cl₂ to give thetitle compound 68 mg (70%) as a green foam. ¹H-NMR (300 MHz, CDCl3) δ7.78 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 6.99-7.03 (mult, 2H),6.82-6.88 (mult, 2H), 5.17 (s, 2H), 4.53-4.57 (mult, 1H), 4.36-4.43 (m,2H), 4.25 (t, J=6.1 Hz, 2H), 3.64-3.74 (mult, 1H), 3.18-3.28 (mult, 1H),3.02 (s, 3H), 1.95 (s, 3H), 1.91 (s, 3H), 1.87 (s, 3H), 1.85-2.06 (mult,2H); mass spectrum (API-TIS) m/z 593 (M-NO), 623 (MH⁺), 640 (MNH₄ ⁺).

Example 13(2Z)-3-(4-Fluorophenyl)-3-[N-methyl-N-[2-methyl-2-(nitrosothio)propyl]carbamoyl]-2-[4-(methylsulfonyl)phenyl]prop-2-enyl acetate 13a.(2Z)-3-(4-Fluorophenyl)-3-[N-methyl-N-[2-methyl-2-sulfanylpropyl]carbamoyl]-2-[4-(methylsulfonyl)phenyl]prop-2-enylacetate

Bis(2-oxo-3oxazolidinyl)phosphonic chloride (0.242 g, 0.55 mmol) wasadded to a solution of the product of Example 12e (0.18 g, 0.46 mmol),triethylamine (0.62 mL, 0.45 g, 4.4 mmol) and 4-(dimethylamino)pyridine(56 mg, 0.46 mmol) in THF (6 mL) at room temperature. After 5 min,1-amino-2-methyl-2-thiopropane (85.6 mg, 0.55 mmol) was added. Theresulting mixture was stirred at room temperature for 16 hours. Thereaction mixture was diluted with EtOAc (50 mL), washed with water,brine, dried over Na₂SO₄, and filtered. Evaporation of the solvent gavea residue that was chromatographed on silica gel eluting with 2%MeOH:CH₂Cl₂ to give the title compound (189 mg, 83%) as a white foam. mp45-47° C. ¹H-NMR (300 MHz, DMSO-d₆) δ 7.44 (d, J=8.4 Hz, 2H), 7.44 (d,J=8.4 Hz, 2H), 7.08-7.11 (mult, 4H), 4.95-5.05 (br s, 2H), 3.60 (s, 2H),3.21 (s, 3H), 3.14 (s, 3H), 2.86 (s, 1H), 1.95 (s, 3H), 1.33 (s, 6H);¹³C NMR (75 MHz, CDCl₃) δ 170.6, 170.2, 160.9, 143.9, 141.0, 139.8,132.7, 131.3, 131.2, 130.6, 127.6, 116.1, 115.8, 65.5, 60.6, 46.5, 44.6,39.4, 31.7, 21.0; mass spectrum (API-TIS) m/z 494 (MH⁺).

13b.(2Z)-3-(4-Fluorophenyl)-3-{N-methyl-N-[2-methyl-2-(nitrosothio)propyl]carbamoyl}-2-[4-(methylsulfonyl)phenyl]prop-2-enylacetate

To a solution of t-BuONO (141 μL of 90% solution, 111 mg, 1.08 mmol) inCH₂Cl₂ (1.4 mL) was added dropwise a solution of the product of Example13a (163 mg, 0.33 mmol) in CH₂Cl₂ (4.3 mL) at 0° C. The resulting greensolution was stirred at 0° C. for 15 min and at room temperature andthen for 15 min in the dark. The residue, after evaporation of thesolvent, was chromatographed on silica gel eluting with 1:1 to 2:1EtOAc:CH₂Cl₂ to give the title compound 60 mg (35%) as a green foam. mp37-38° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.80 (d, J=8.3 Hz, 2H), 7.35 (d,J=8.3 Hz, 2H), 7.04-7.08 (mult, 2H), 6.85-6.90 (mult, 2H), 4.96 (s, 2H),4.25 (s, 2H), 3.04 (s, 3H), 2.95 (s, 3H), 2.04 (s, 3H), 1.92 (s, 6H);¹³C NMR (75 MHz, CDCl₃) δ 170.6, 170.5, 164.2, 160.9, 143.7, 140.6,139.8, 133.0, 131.2, 131.1, 130.5, 130.2, 127.5, 116.1, 115.8, 65.4,58.2, 57.8, 44.5, 39.3, 27.9, 20.9; mass spectrum (API-TIS) m/z 493(M-NO), 523 (MH⁺), 540 (MNH₄ ⁺).

Example 14 2-[1-Methyl4-(nitrosothio)4-piperidyl]ethyl(2Z)-3-(4-acetyloxy-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]but-2-enoate14a. 2-[1-Methyl-4-(nitrosothio)-4-piperidyl]ethyl(2Z)-3-(4-acetyloxy-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]but-2-enoate

DCC (0.11 g, 0.53 mmol) in CH₂Cl₂ (5 mL) was added dropwise to a stirredsolution of the product of Example 12e (0.21 g, 0.53 mmol),2-[1-methyl-4-(nitrosothio)-4-piperidyl]ethan-1ol (prepared as describedin Patent Application WO/025776, (the disclosure of which isincorporated by reference herein in its entirety) Example 13d, 0.132 g,0.64 mmol) and 4-(dimethylamino)pyridine (33 mg, 0.27 mmol) in CH₂Cl₂ (5mL) at room temperature. The resulting suspension was stirred at roomtemperature for 16 hours then the precipitate was filtered and washedwith CH₂Cl₂ (10 mL). The combined organic phase was dried over Na₂SO₄and filtered. The residue after evaporation of the solvent waschromatographed on silica gel eluting with 2% MeOH:CH₂Cl₂ to give thetitle compound 13 mg (4%) as a green oil. ¹H-NMR (300 MHz, CDCl₃) δ 7.76(d, J=8.4 Hz, 2H), 7.28 (d, J=9.1 Hz, 2H), 6.94-6.98 (mult, 2H),6.81-6.86 (mult, 2H), 5.15 (s, 2H), 4.42 (t, J=6.7 Hz, 2H), 3.00 (s,3H), 2.68 (t, J=6.8 Hz, 2H), 2.30 (s, 3H), 2.15-2.43 (mult, 8H), 1.93(s, 3H); mass spectrum (API-TIS) m/z 549 (M-NO), 579 (MH⁺).

Example 15(3Z)-4-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-[4-(methylsulfonyl)phenyl]but-3-enoic acid 15a.(3Z)4(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-[4-(methylsulfonyl)phenyl]but-3-enoicacid

This compound was synthesized as described in U.S. Pat. No. 5,807,873,(the disclosure of which is incorporated by reference herein in itsentirety), Example 63. ¹H-NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.2 Hz, 2H),7.40 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H),4.03 (q, J=7.1 Hz, 2H), 3.45 (s, 2H), 3.10 (s, 3H), 0.97 (t, J=7.1 Hz,3H); mass spectrum (API-TS) m/z 377 (M-CO₂), 423 (MH⁺), 440 (MH⁺), 445(MNa⁺).

15b. 2-Bromo-1-(1,1,2,2-tetramethyl-1-silapropoxy)ethane

t-Butyldimethylchlorosilane (21.7 g, 144 mmol) in dry THF (50 mL) wasadded dropwise to a solution of 1,2-bromoethanol (18 g, 144 mmol) andimidazole (9.81 g, 144 mmol) in dry THF (50 mL) at room temperature. Theresulting white suspension was stirred at room temperature for 16 hours.The reaction mixture was diluted with EtOAc (200 mL), washed with water,brine, dried over Na₂SO₄, filtered and concentrated in vacuo at roomtemperature to give the title compound 33.2 g (96%) as a colorlessliquid. ¹H-NMR (300 MHz, CDCl₃) δ 3.89 (t, J=6.5 Hz, 2H), 3.39 (t, J=6.6Hz, 2H), 0.90 (s, 9H), 0.10 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 63.7,60.5, 33.4, 26.0, 21.2, 14.3, −5.1.

15c.4-{1-Methyl-1-[(2,4,6-trimethoxyphenyl)methylthio]ethyl}-3-[2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl]-1,3-oxazolidin-2-one

NaH (1.6 g, 66.7 mmol) was added portionwise to a solution of theproduct of Example 12h (15.3 g, 44.9 mmol) in dry DMF (50 mL) undernitrogen at 0° C. The resulting suspension was stirred at 0° C. for 20min to give a brown red solution. The product of Example 15b (12.9 g,53.8 mmol) in DMF (10 mL) was added dropwise and stirred at roomtemperature for 16 hours. The solvent was evaporated. The residue waspartitioned with 1:1 EtOAc:water and the organic layer was separated.The aqueous layer was extracted with EtOAc and the combined organiclayers were washed with water, dried over Na₂SO₄, and filtered. Theresidue after evaporation of the solvent was chromatographed on silicagel eluting with 1:1 EtOAc:Hexane to give the title compound (18 g, 80%)as a white foam. ¹H-NMR (300 MHz, CDCl₃) δ 6.12 (s, 2H), 4.38-4.47(mult, 1H), 4.09-4.21 (mult, 3H), 3.83 (s, 9H), 3.79 (s, 2H), 3.71-3.79(mult, 2H), 3.42-3.53 (m, 1H), 1.50 (s, 3H), 1.29 (s, 3H), 0.95 (s, 9H),0.08 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 160.8, 159.7, 158.9, 106.5,90.9, 65.9, 62.3, 60.5, 56.0, 55.5, 48.6, 47.5, 26.4, 26.0, 22.6, 21.2,20.3, 18.3, 14.4, −5.3; mass spectrum (API-TIS) m/z 500 (MH⁺).

15d.3-(2-Hydroxyethyl)-4-(1-methyl-1-sulfanylethyl)-1,3-oxazolidin-2-one

The product of Example 15c (14.9 g, 29.8 mmol) was treated with water(11.8 mL), phenol (11.8 g), anisole (11.8 mL) and finallytrifluoroacetic acid (147 mL). The resultant solution was stirred atroom temperature for 1 hour and then the solvent was evaporated to givea yellow oil which was chromatographed on silica gel eluting with 1:1EtOAc:Hexane to 5% MeOH:CH₂Cl₂ to give the title compound 4.2 g (69%) asa pale yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 4.33-4.43 (mult, 2H),3.72-3.92 (mult, 4H), 3.50-3.59 (mult, 1H), 2.55-2.80 (br s, 1H), 1.78(s, 1H), 1.41 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 160.6, 66.2, 66.0,60.4, 48.3, 47.6, 29.0, 27.8; mass spectrum (API-TIS) m/z 206 (MH⁺), 223(MNH₄ ⁺). Anal. Calcd for C₈H₁₅NO₃S: C, 46.81; H, 7.37; N, 6.82. Found:C, 46.81; H, 7.11; N, 6.61.

15e.3-(2-Hydroxyethyl)-4-[1-methyl-1-(nitrosothio)ethyl]-1,3-oxazolidin-2-one

To a solution of t-butyl nitrite (4.45 mL of 90% solution, 3.5 g, 34.1mmol) in CH₂Cl₂ (28 mL) was added dropwise a solution of the product ofExample 15d (3.88 g, 18.9 mmol) in CH₂Cl₂ (58 mL) at 0° C. The resultinggreen solution was stirred at 0° C. for 1 hour and then at roomtemperature for 20 min in the dark. The residue after evaporation of thesolvent was chromatographed on silica gel eluting with 1:1 EtOAc:CH₂Cl₂to 5% MeOH:CH₂Cl₂ to give the title compound 3.7 g (84%) as a green oil.¹H-NMR (300 MHz, CDCl₃) δ 4.70-4.74 (mult, 1H), 4.41-4.52 (mult, 2H),3.77-3.89 (mult, 3H), 3.44-3.50 (mult, 1H), 1.99 (s, 3H), 1.96 (s, 3H);¹³C NMR (75 MHz, CDCl₃) δ 160.4, 65.8, 63.9, 60.0, 59.3, 48.1, 25.7,24.8; mass spectrum (API-TIS) m/z 205 (M-NO), 235 (MH⁺), 252 (MNH₄ ⁺).Anal. Calcd for C₈H₁₄N₂O₄S: C, 41.02; H, 6.02; N, 11.96. Found: C,41.30; H, 5.87; N, 11.68.

15f.(3Z)-4-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-[4-(methylsulfonyl)phenyl]but-3-enoicacid

DCC (32 mg, 0.155 mmol) in CH₂Cl₂ (0.5 mL) was added dropwise to astirred solution of the product of Example 15a (66 mg, 0.155 mmol), theproduct of Example 15e (36 mg, 0.154 mmol) and 4-(dimethylamino)pyridine(19 mg, 0.155 mmol) in CH₂Cl₂ (2 mL) at 0° C. The resulting suspensionwas stirred at 0° C. for 15 min and then at room temperature for 1.5hours. The precipitate was filtered and washed with CH₂Cl₂ (5 mL). Thecombined organic phases were dried over Na₂SO₄ and filtered. The residueafter evaporation of the solvent was chromatographed on silica geleluting with 1:3 EtOAc:CH₂Cl₂ to give the title compound 69 mg (70%) asa green solid. mp 40-42° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.96 (d, J=6.7 Hz,2H), 7.39 (d, J=6.6 Hz, 2H), 7.28-7.31 (mult, 2H), 7.04-7.07 (mult, 2H),4.69-4.73 (m, 1H), 4.01-4.47 (m, 2H+2H+1H), 3.98 (q, J=7.1 Hz, 2H),3.42-3.50 (mult, 1H), 3.37 (s, 2H), 3.09 (s, 3H), 1.96 (s, 3H), 1.93 (s,3H), 0.93 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 170.7, 168.3,159.1, 149.3. 145.6. 149.7. 139.4, 134.6, 130.0, 128.6, 128.0, 126.9,65.4, 62.6, 61.3, 61.3, 59.1, 44.5, 44.3, 37.9, 25.2, 25.1, 13.6; massspectrum (API-TIS) m/z 609 (M-NO), 639 (MH⁺), 659 (MNH₄ ⁺). Anal. Calcdfor C₂₈H₃₁ClN₂O₉S: C, 52.62; H, 4.89; N, 4.38; Cl, 5.55; S, 10.03.Found: C, 52.40; H, 4.98; N, 4.17; Cl, 5.68, S, 9.80.

Example 163-Methyl-N-{[4-(5-methyl-3-phenylisoxazol4-yl)phenyl]sulfonyl}-3-(nitrosothio)butanamide16a.3-Methyl-N-{[4-(5-methyl-3-phenylisoxazol)phenyl]sulfonyl}-3-{(2,4,6-trimethoxyphenyl)methylthiobutanamide

3-Methyl-3-[(2,4,6-trimethoxyphenyl)methylthio]butanoic acid (preparedas described in patent application WO 97/34871, (the disclosure of whichis incorporated by reference herein in its entirety), Example 1a, 1.05g, 3.37 mmol) was added to a stirred solution of4-(5-methyl-3-phenylisoxazol)benzene sulfonamide (prepared as describedby Talley et. al., J. Med. Chem. 43, 775 (2000), (the disclosure ofwhich is incorporated by reference herein in its entirety), 0.85 g, 2.70mmol), 4-(dimethylamino)pyridine (0.1 g) in THF (30 mL). The resultingsolution was stirred at room temperature for 15 min and then solid DCC(0.84 g, 4.04 mmol) was added. The reaction mixture was stirred at roomtemperature for 3 hours, the solid was then removed by filtration. Thefiltrate was concentrated and the residue was chromatographed on silicagel eluting with 1:1 EtOAc:Hexane to give the title compound (0.92 g,56%) as a white solid. mp 138-140° C. ¹H-NMR (300 MHz, CDCl₃) δ 9.98 (s,1H), 7.93 (d, J=8.4 Hz, 2H), 7.25-7.42 (mult, 7H), 6.20 (s, 2H), 3.92(s,6H), 3.83 (s, 3H), 3.79 (s, 2H), 2.54 (s, 2H), 2.45 (s, 3H), 1.20 (s,6H); ¹³C-NMR (75 MHz, CDCl₃) δ 168.8, 167.3, 161.0, 158.5, 138.0, 136.1,129.8, 129.7, 128.9, 128.7, 128.4, 114.5, 105.2,91.1, 56.1, 55.4, 47.3,43.8, 29.0, 21.1, 11.7; mass spectrum (API-TIS) m/z 611 (MH⁺).

16b.3-Methyl-N-{[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl}-3-sulfanylbutanamide

The product of Example 16a (0.6 g, 0.98 mmol) in CH₂Cl₂ (5 mL) was addedto a stirred solution of cysteine (1.1 g, 9.07 mmol) in TFA (5 mL) andthe resulting pale yellow solution was stirred at room temperature for 1hour. Crushed ice (˜3 g) was added and the mixture neutralized withconcentrated NH₄OH (8 mL). The aqueous mixture was extracted with EtOAc(3×25 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated to give the title compound (0.4 g, 95%) as a viscous oil.This material was used in the next reaction without furtherpurification. mp 138-140° C. ¹H-NMR (300 MHz, CDCl₃) δ 8.05 (d, J=8.3Hz, 2H), 7.30-7.40 (mult, 7H), 2.57 (s, 2H), 2.49(s, 3H), 2.09 (s, 1H),1.37 (s, 6H); ¹³C-NMR (75 MHz, CDCl₃) δ 168.5, 167.5, 161.1, 137.6,136.3, 130.0, 129.7, 128.8, 128.7, 128.4, 128.1, 114.4, 52.0,42.0,32.4,11.7; mass spectrum (API-TIS), m/z 431 (MH⁺).

16c.3-Methyl-N-{[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]-3-(nitrosothio)butanamide

A few drops of HCl in ether was added to a stirred solution of productof Example 16b (0.4 g, 0.93 mmol) in CH₂Cl₂ (5 mL) and MeOH (5 mL). t-BuONO (90%, 120 mL, 0.93 mmol) was then added. The resulting olivegreen solution was stirred at room temperature for 15 min undernitrogen. Cold water (25 mL) was added and the product was extractedinto EtOAc (2×25 mL). The organic layer was dried over Na₂SO₄ andconcentrated. Flash chromatography of the residue on silica gel elutingwith 1:1 EtOAc/Hexane gave the title compound (0.32 g, 75%) as a greenfoam. ¹H-NMR (300 MHz, CDCl₃) δ 9.38 (s, 1H), 7.96 (d, J=8.4 Hz, 2),7.28-7.43 (mult, 7H), 3.22 (s, 2H), 2.52 (s, 3H), 1.98 (s, 6H); ¹³C-NMR(75 MHz, CDCl₃) δ 167.8, 167.6, 161.1, 137.4, 136.2, 130.0, 129.8,128.7, 128.5, 128.0, 114.4, 53.6, 48.3, 27.8, 11.6; mass spectrum(API-TIS), m/z 460 (MH⁺).

Example 172-Methyl-2-(nitrosothio)propyl-5-(4-chlorophenyl)-1-(4-sulfamoylphenyl)pyrazole-3-carboxylate17a. Methyl5-(4-chlorophenyl)-1-(4-sulfamoylphenyl)pyrazole-3-carboxylate

This compound was prepared as described in Penning et. al. J. Med. Chem.40, 1347-1365 (1997), (the disclosure of which is incorporated byreference herein in its entirety), Compound 3a. mp 186° C. ¹H-NMR (300MHz, DMSO-d₆) δ 7.89 (d, J=8.6 Hz, 2H), 7.6-7.4 (m, 6H), 7.32 (d, J=8.6Hz, 2H), 7.21 (s, 1H), 3.87 (s, 3H); mass spectrum (API-TIS) m/z 392(MH+).

17b. 5-(4-Chlorophenyl)-1-(4-sulfamoylphenyl)pyrazole-3-carboxylic acid

A stirred mixture of the product of Example 17a (9.75 g, 24.9 mmol),aqueous NaOH (1.5 N, 60 mL), and THF (200 mL) was heated to reflux for 5hours. The reaction mixture was concentrated on a rotary evaporator. Theresidue was partitioned between EtOAc (200 mL) and 2N aqueous HCl (100mL). The organic layer was separated and washed with water, dried overNa₂SO₄, filtered, and concentrated to give a solid material.Crystallization from EtOH/THF (1:1) gave the title compound (8.8 g, 90%)as an off-white solid. mp 203° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.02 (d,J=8.4 Hz, 2H), 7.7-7.6 (m, 4H), 7.45 (d, J=8.4 Hz, 2H), 7.28 (s, 1H);mass spectrum (API-TIS) m/z 378 (MH+).

17c. 2-methyl-2-sulfanylpropan-1-ol

To 2-methylpropanal (3.53 g, 49 mmol) in carbon tetrachloride (30 ml)was added sulfur monochloride (2 ml, 25 mmol) and the reaction mixturewas stirred at 55° C. for 2 hours. After cooling to room temperature,the volatiles were evaporated in vacuo to give2-[(1,1-dimethyl-2-oxoethyl)disulfanyl]-2-methylpropanal. The disulfide(17.5 g, 85.7 mmol) was dissolved in THF (100 ml) and LiAlH₄ (86 ml,1M/THF) was added slowly. After stirring at room temperature for 1 hour,the mixture was poured onto ice, treated with 3N HCl (150 ml) and thenextracted with EtOAc. The organic extracts were dried over sodiumsulfate and the volatiles were evaporated to yield 12.8 g (71%) of thetitle compound as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 3.44 (s,2H), 2.25 (brs, 1H), 1.63 (s, 1H), 1.36 (s, 6H); ¹³C NMR (CDCl₃) 73.3,46.3, 28.3.

17d. 2-methyl-2-(nitrosothio)propan-1-ol

To a solution of the product Example 17c (4.4 g, 41.5 mmol) in CH₂Cl₂(50 ml) was added t-BuONO (5.5 ml, 41.5 mmol). The reaction mixture wasstirred at room temperature for 10 minutes and the volatiles wereevaporated in vacuo at 40° C. to give 4.6 g (82%) of the title compoundas a dark green oil. ¹H NMR (300 MHz, CDCl₃) δ 4.17 (s, 2H), 1.95 (brs,1H), 1.90 (s, 6H); ¹³C NMR (CDCl₃) 70.5, 57.7, 25.1.

17e.2-Methyl-2-(nitrosothio)propyl-5-(4-chlorophenyl)-1-(4-sulfamoylphenyl)pyrazole-3-carboxylate

To a stirred solution of the product of Example 17b (3.78 g, 10.0 mmol),the product of Example 17d (1.35 g, 10.0 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.83 g,20.0 mmol), and 4-(dimethylamino)pyridine (10 mg) in DMF (80 mL) wasadded triethylamine (2.79 mL, 20.0 mmol). After being stirred at roomtemperature for 4 hours, the mixture was diluted with EtOAc (200 mL),washed with 1N HCl, water, dried over Na₂SO₄, filtered, andconcentrated. Chromatography of the residue on silica gel eluting with1:4 EtOAc:Hexane gave the title compound (0.20 g, 4%) as a green solid.mp 153° C. (dec). ¹H NMR (300 MHz, DMSO-d₆) δ 7.88 (d, J=8.6 Hz, 2H),7.55-7.49 (m, 4H), 7.32 (d, J=8.6 Hz, 2H), 7.20 (s, 1H), 3.32 (s, 2H),1.82 (s, 6H); mass spectrum (API-TIS) m/z 495 (MH⁺). Anal. Calcd. forC₂₀H₁₉ClN₄O₅S₂: C, 48.53; H, 3.87; N, 11.32; Cl, 7.16; S, 12.96. Found:C, 48.79; H, 4.12; N, 11.50; Cl, 6.81; S, 12.76.

Example 184-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-({4-[(nitroxy)methyl]phenyl}methyl)-2-hydroxypyridazin-3-one18a.4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-benzyl-2-hydropyridazin-3-one

This compound was synthesized as described in patent application WO99/10331, (the disclosure of which is incorporated by reference hereinin its entirety), Example 10. m.p. 151-153° C. ¹H-NMR (300 MHz, CDCl₃) δ7.85 (d, J=8.4 Hz, 2H), 7.83 (m, 1H), 7.53 (m, 2H), 7.31 (m, 5H), 7.15(m, 2H), 6.93 (m, 2H), 5.93 (s, 2H), 3.02 (s, 3H); ¹³C-NMR (75 MHz,CDCl₃) δ 164.3, 161.0, 159.5, 140.5, 138.7, 13706, 135.8, 132.5, 132.4,129.9, 129.1, 128.6, 128.1, 127.7, 115.2, 115.2,56.1,44.2; mass spectrum(API-TIS) m/z 435 (MH⁺).

18b.4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-hydropyridazin-3-one

To the product of Example 18a (74 mg, 0.17 mmol) in toluene (20 mL) wasadded AlBr₃ (140 mg, 0.52 mmol). The reaction mixture was heated at 90°C. for 15 minutes and then cooled to 0° C. The reaction mixture was thenpoured into ice cold water, acidified with 1 N HCl and extracted withethyl acetate (2×50 mL). The combined extracts were washed with water(2×25 mL) and brine (1×25 mL), dried over Na₂SO₄ and filtered.Evaporation of the solvent gave a residue that was purified by columnchromatography on silica gel eluting with 5% methanol in CH₂ Cl₂ to givethe title compound (45 mg, 76%). ¹H NMR (300 MHz, CDCl₃) δ 7.8-7.9 (m,3H), 7.35 (d, J=9 Hz, 2H), 7.2 (m, 2H), 7.0 (t, J=9 Hz, 2H), 3.05 (s,3H); LRMS (APIMS) m/z 345 (M+H)⁺.

18c. Methyl4-({5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-oxohydro-pyridazinyl}methyl)benzoate

The product of Example 18b (210 mg, 0.61 mmol) was dissolved inanhydrous DMF (3 mL) and then K₂CO₃ (336 mg, 2.44 mmol) was added. Tothis reaction mixture was added methyl 4-(bromomethyl)benzoate (140 mg,0.61 mmol) and the mixture was stirred at room temperature overnight.The reaction mixture was diluted with water (25 mL) and extracted withethyl acetate (2'50 mL). The combined extracts were washed with water(4×50 mL), brine (1×25 mL), and dried over sodium sulfate. Evaporationof the solvent gave a residue that was purified by column chromatographyon silica gel eluting with 1:1 EtOAc:Hexane to gave the title compound(210 mg, 70%) as a colorless foam. ¹H-NMR (300 MHz, CDCl₃) δ 8.02 (d,J=7.8 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.84 (s, 1H), 7.58 (d, J=7.8 Hz,2H), 7.32 (t, J=7.9 Hz, 2H), 7.15 (t, J=6.8 Hz, 2H), 6.94 (t, J=8.2 Hz,2H), 5.43 (s, 2H), 3.89 (s, 3H), 3.03 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ166.7, 164.5, 159.5, 140.8, 140.7, 140.4, 138.8, 137.4, 137.3, 132.5,132.4, 130.0, 129.9, 129.0, 128.3, 127.8, 127.4, 115.3, 55.8, 52.1,44.3; mass spectrum (API-TIS)) m/z 493 (MH⁺).

18d.4-(4-Fluorophenyl)-2-14-(hydroxymethyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-2-hydroxypyridazin-3-one

The product of Example 18c (190 mg, 0.386 mmol) was dissolved inanhydrous CH₂C₂ (10 mL). The solution was cooled to 0° C. and 1M DIBAL-H(1.05 mL) was added dropwise under nitrogen atmosphere. The reactionmixture was stirred at 0° C. for 30 minutes and then at room temperaturefor 15 minutes. It was then quenched with ice cold water, acidified with1 N HCl, and extracted with CH₂Cl₂ (2×50 mL). The combined extracts werewashed water (2×25 mL), brine (1×25 mL) and then dried over Na₂SO₄.Evaporation of the solvent gave a residue that was purified by columnchromatography on silica gel eluting 5% methanol in CH₂Cl₂ to give thetitle compound (100 mg, 54%) as a colorless foam. mp 155-164° C. ¹H-NMR(CDCl₃) δ 7.86 (d, J=8.2 Hz, 2H), 7.82 (s, 1H), 7.52 (d, J=7.8 Hz, 2H),7.34 (d, J=7.9 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.14 (t, J=7.6 Hz, 2H),6.93 (t, J=8.5 Hz, 2H), 5.38 (s, 2H), 4.65 (s, 2H), 3.03 (s, 3H); ³C-NMR(300 MHz, CDCl₃) δ 164.4, 161.1, 159.5, 140.9, 140.7, 140.5, 138.8,137.2, 135.1, 132.4, 129.9, 129.4, 127.7, 127.6, 115.6,115.3,64.8,55.9,44.3; mass spectrum (API-TIS) m/z 465 (MH⁺).

18e.4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-({4-[(nitroxy)-methyl]phenyl}methyl)-2-hydroxypyridazin-3-one

The product of Example 18d (30 mg, 0.065 mmol) was dissolved inanhydrous ethyl acetate (0.5 mL). In a separate flask the nitratingmixture was prepared by adding successively acetic anhydride (472 νL,5.20 mmol) and fuming nitric acid (137 μL, 3.25 mmol) at 0° C. From thismixture, 65 μL was added to the above solution cooled to 0° C. Thereaction mixture was stirred at 0° C. for 5 minutes and quenched withwater and then extracted with ethyl acetate. The organic layer wasseparated, washed with water, brine, and dried over Na₂SO₄. Evaporationof the solvent gave a residue that was purified by preparative thinlayer chromatography (0.25 mm thick silica gel plate) using 6:4EtOAc:Hexane to give the title compound (5.5 mg, 17%) as a white solid.mp 78-87° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.86 (d, I ═8.2 Hz, 2H), 7.84 (s,1H), 7.58 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.2 Hz,2H), 7.15 (t, J=6.4 Hz, 2H), 6.95 (t, J=8.6 Hz, 2H), 5.41 (s, 2H), 5.40(s, 2H), 3.04 (s, 3H); mass spectrum (API-TIS) m/z 510 (MH⁺).

Example 194-(Methylsulfonyl)-1-{1-(nitrooxy)ethyl]-4-benzylpyrazol-5-yl}benzene19a. 1-(4-Methylthiophenyl)-3-phenylpropan-1-one

To a stirred solution of 4-(methylthio)benzonitrile (25.0 g, 0.17 mol)in THF (100 mL) under N₂ atmosphere was added phenethylmagnesiumchloride (1.0 M in THF, 210 mL, 0.21 mol). The solution was heated toreflux for 4 hours, cooled to 0° C., and quenched carefully with water(10 mL). The resulting slurry was treated with 6 N hydrochloric acid(200 mL) and stirred at room temperature overnight. The THF wasevaporated from the mixture, and the residue was extracted with EtOAc(2×300 mL). The combined organic extracts were washed with 2M NA₂CO₃,dried over Na₂SO₄, filtered, and concentrated to give a solid material.Recrystallization from EtOAc-Hex (1:4) afforded the title compound (41.5g, 96%) as greenish plates. mp 105° C. ¹H NMR (300 MHz, CDCl₃) δ 7.85(d, J=8.5 Hz, 2H), 7.32-7.19 (m, 7H), 3.24 (t, J=6.8 Hz, 2H), 3.06 (t,J=6.8 Hz, 2H), 2.50 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 198.2, 145.8,141.3, 133.2, 128.48, 128.42, 128.38, 126.1, 125.0,40.2,30.2, 14.7; massspectrum (API-TIS) m/z 257 (M+H).

19b. Mixture of 2-[3-(4-methylthiophenyl)-4-benzylpyrazolyl]ethan-1-oland 2-[5-(4-methylthiophenyl)-4-benzylpyrazolyl]ethan-1-ol

To a stirred solution of the product of Example 19a (850 mg, 3.3 mmol)in THF (8 mL) at −78° C. under N₂ atmosphere was added lithiumdiisopropylamide (1.5 M in cyclohexane, 2.66 mL, 4.0 mmol) dropwise.After 30 min, a solution of HCO₂Et (0.32 mL, 4.0 mmol) in THF (1 mL) wasadded, and the reaction was allowed to gradually warm to roomtemperature and stirred overnight. The mixture was poured into 1 N HCl(10 mL), and extracted with EtOAc (2×20 mL). The combined organicextracts were washed with saturated NaHCO₃ (10 mL), dried over Na₂SO₄,filtered, and concentrated to give an off-white solid (905 mg). Astirred solution of this solid and 2-hydoxyethylhydrazine (0.37 mL, 5.00mmol) in ETOH (15 mL) was heated to reflux under N₂ for 3 hours, andthen concentrated. The residue was dissolved in EtOAc (50 mL), washedwith 1N HCl, dried over Na₂SO, filtered, and concentrated. The residuewas chromatographed on silica gel eluting with EtOAc to give tworegioisomeric pyrazoles as an inseparable mixture (0.81 g, 75% over twosteps). Ratio of isomers 3:2 as judged by the proton NMR. ¹H NMR (300MHz, CDCl₃) δ 7.53-7.09 (m, ArH), 4.17 (t, J=4.5 Hz), 4.08 (t, J=4.5Hz), 3.98 (t, J=5.0 Hz), 3.96 (s), 3.91 (t, 5.0 Hz), 3.71 (s), 2.51 (s),2.49 (s); mass spectrum (API-TIS) m/z 325 (M+H).

19c and 19d.1-[1-(2-Hydroxyethyl)-4-benzylpyrazol-5-yl]-4-(methylsulfonyl)benzeneand1-[1-(2-Hydroxyethyl)-4-benzylpyrazol-3-yl]-4-(methylsulfonyl)benzene

The product of Example 19b (810 mg, 2.50 mmol) was dissolved in MeOH (15mL), and treated with oxone (4.61 g, 7.50 mmol) and water (10 ml). Theslurry was stirred at room temperature for 30 min. The reaction mixturewas poured into water (20 mL), neutralized with aqueous NACO, andextracted with EtOAc (50 mL×2). The combined organic extracts were driedover Na₂SO₄, filtered, and concentrated. The residue was chromatographedon silica gel eluting with EtOAc to give first compound Example 19c (450mg, 50%) followed by Example 19d (260 mg, 29%). Physical data forExample 19c: R_(f)0.47 (EtOAc, silica gel). mp 96° C. ¹H NMR (300 MHz,CDCl₃) δ 7.93 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.6 Hz, 2H), 7.31-7.17 (m,6H), 4.23 (t, J=4.5 Hz, 2H), 4.03 (t, J=4.5 Hz, 2H), 4.00 (s, 2H), 3.05(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 147.7, 139.9, 139.1, 138.8, 131.8,128.6, 128.3, 128.0, 127.4, 126.3, 118.6, 61.6, 54.0, 44.4, 30.7; massspectrum (API-TIS) m/z 357 (M+H). Anal. calcd for C₁₉H₂₀N₂O₃S: C, 64.02,H, 5.66; N, 7.86, S, 9.00. Found: C, 63.80; H, 5.76; N, 8.10; S, 8.98.Physical data for Example 19d: R_(f)0.38 (EtOAc, silica gel). mp 68° C.¹H NMR (300 MHz, CDCl₃) δ 7.99 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz,2H), 7.41 (s, 1H), 7.25-7.14 (m, 3H), 7.06 (d, J=7.2 Hz, 2H), 4.07 (t,J=4.6 Hz, 2H), 3.93 (t, J=4.6 Hz, 2H), 3.72 (s, 2H), 3.09 (s, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 140.5, 140.3, 139.6, 139.5, 135.3, 130.9, 128.3,128.1, 127.5, 126.0, 119.1,61.3,51.1, 44.2,29.8; mass spectrum (API-TIS)m/z 357 (M+H). Anal. calcd for C₁₉H₂₀N₂O₃S: C, 64.02, H, 5.66; N, 7.86,S, 9.00. Found: C, 64.18; H, 5.87; N, 7.79; S, 8.94.

19e.4-(Methylsulfonyl)-1-{1-[2-(nitrooxy)ethyl]-4-benzylpyrazol-5-yl}benzene

Fuming HNO₃ (90%, 1 mL) was added to Ac₂O (5 mL) at 0° C., and theresulting mixture was stirred for 10 minutes. The product of Example 19d(235 mg, 0.66 mmol) in EtOAc (6 mL) was added, and the solution wasstirred at 0° C. for 5 min. The mixture was poured into ice-cooledsaturated NaHCO₃ (10 mL), extracted with EtOAc (2×20 mL). The combinedorganic extracts were repeatedly washed with brine, dried over Na₂SO₄,filtered, and concentrated to afford the title product as oil (259 mg,96%). ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4Hz, 2H), 7.24-7.18 (m, 4H), 7.06 (m, 2H), 4.77 (t, J=5.0 Hz, 2H), 4.31(t, J=5.0 Hz, 2H), 3.72 (s, 2H), 3.10 (s, 3H); mass spectrum (API-TIS)m/z 402 (M+H).

Example 204-{1-Cyclohexyl-3-[(nitrooxy)methyl]pyrazol-5-yl}-1-methylsulfonyl)benzene 20a. Methyl(2Z)-2-hydroxy-4-(4-methylthiophenyl)-4-oxobut-2-enoate

Dimethyloxalate (26 g, 180.7 mmol) was added to a stirred suspension ofsodium methoxide (9.75 g, 180.7 mmol) in dry toluene (200 mL) at 0° C.The white suspension was stirred for 15 min at 0° C. A solution of4′-(methylthio)acetophenone (15 g, 90.4 mmol) in dry toluene (150 mL)was then added dropwise over 15 min giving a yellow suspension which wasstirred for 2 hours at room temperature. The thick yellow suspension wastransferred to a 2 liter flask and stirred vigorously with 10% HCl (250mL) and EtOAc (200 mL) to dissolve all the solids present. The organiclayer was separated and the aqueous layer was extracted with EtOAc (100mL). The combined organic extracts were washed with water (250 mL),dried over Na₂SO₄ and the solvent was evaporated under reduced pressureto give thick brown oil. The brown oil was dissolved in CH₂Cl₂ (25 mL)and hexane (125 mL) and left in a freezer at −20° C. for 16 hours togive the title compound (18 g, 79%) as orange color solid. mp 81° C.¹H-NMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz,2H), 6.97 (s, 1H), 3.89 (s, 3H), 2.47 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃);mass spectrum (API-TIS) m/z 253 (MH⁺)

20b. Methyl-1-cyclohexyl-5-(4-methylthiophenyl)pyrazole-3-carboxylate

A mixture of the product of Example 20a (1.98 g, 7.8 mmol) andcyclohexylhydrazine hydrochloride (1.54 g, 10.2 mmol) in methanol (40mL) was heated at 70° C. for 3 hours and cooled to room temperature. Themixture was made basic with 10% Na₂CO₃ and extracted with EtOAc (3×25mL). The organic extracts were dried over Na₂SO₄ and the solvent wasevaporated under reduced pressure to give a thick oil. The oil wasdissolved in CH₂Cl₂ (4 mL) and hexane (20 mL) and left in a freezer at−10° C. for 16 hours to give the title compound (2.2 g, 85%) as a whitesolid. mp 84° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.33 (d, J=8.3 Hz, 2H), 7.26(d, J=8.3 Hz, 2H), 6.76 (s, 1H), 4.08-4.13 (mult, 1H), 3.93 (s, 3H),2.54 (s, 3H), 2.07-2.20 (mult, 2H), 1.80-1.95 (mult, 4H), 1.62-1.72(mult, 1H), 1.20-1.30 (mult, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 163.1,143.6, 142.3, 140.1, 129.4, 126.4, 126.2, 108.8, 58.7, 51.9, 33.1, 25.5,24.8, 15.3; mass spectrum (API-TIS), m/z 331 (MH⁺). Anal. calcd forC₁₈H₂₂N₂O₂S: C, 65.43; H, 6.71; N, 8.48; S, 9.70 Found: C, 65.28; H,6.66; N, 8.47; S, 9.61.

20c. 1-Cyclohexyl-5-(4-methylthiophenyl)pyrazole-3-yl]methan-1-ol

A solution of lithium aluminum hydride (2 mL at 1 M, 2 mmol) was addedto a stirred solution of the product of Example 20b (0.7 g, 2.1 mmol) inTHP (15 mL) at 0° C. The resulting clear solution was stirred at roomtemperature for 1 hour. Solid Na₂SO₄.10H₂O (2 g) was added in smallportions with stirring until a thick precipitate formed. Methanol inCH₂Cl₂ (10%, 50 mL) was added and the mixture was filtered. The solidwas washed with additional methanol in CH₂Cl₂ (10%, 50 mL) and thecombined filtrates were evaporated to give the title compound (0.61 g,95%) as a white solid. mp 97° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.31 (d,J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 6.20 (s, 1H), 4.71 (d, J=4.8 Hz,2H), 4.00-4.15 (mult, 1H), 2.53 (s, 3H), 1.65-2.10 (mult, 7H), 1.15-1.30(mult, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 151.0, 143.2, 139.3, 129.3, 127.5,126.3, 104.1, 59.0, 57.7, 33.2, 25.6, 25.1, 15.4; mass spectrum (API-HS)m/z 303 (MH⁺).

20d.4-[1-Cyclohexyl-3-(hydroxymethyl)pyrazol-5-yl]-1-(methylsulfonyl)benzene

The product of Example 20c (0.6 g, 2.0 mmol) was dissolved in a mixtureof MeOH (20 mL) and water (8 mL) and cooled to 0° C. Solid oxone (3 g)was added and the resulting suspension was stirred at 0° C. for 1 hr.Water (25 mL) and 15% NH₄OH (25 mL) were added. The mixture wasextracted with ETOAC (3×25 mL) and the organic extracts were dried overNa₂SO₄. The solvent was evaporated under reduced pressure to give whitesolid which was recrystallized from CH₂Cl₂ (5 mL) and hexane (20 mL) togive the title compound (0.62 g, 94%) as a white solid. mp 148° C.¹H-NMR (300 MHz, CDCl₃) δ 8.03 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.3 Hz,2H), 6.31 (s, 1H), 4.73 (s, 2H), 3.90-4.10 (mult, 1H), 3.13 (s, 3H),2.45 (s, 1H, OH), 1.66-2.05 (mult, 7H), 1.10-1.25 (mult, 3H); ¹³C-NMR(75 MHz, CDCl₃) δ 151.4, 141.7, 140.4, 136.5, 129.7, 127.9, 105.0, 59.0,58.2, 44.4, 33.3, 25.6, 25.0; mass spectrum (API-TIS),m/z 335 (MH⁺).

20e.4-{1-Cyclohexyl-3-(nitrooxy)methyl]pyrazol-5-yl}-1-(methylsulfonyl)benzene

Fuming HNO₃ (0.76 mL, 18 mmol) was added to Ac₂O (2.7 mL, 28.8 mmol) at0° C. via syringe and stirred for 5 min at 0° C. The mixture was thentransferred with a pasteur pipette to a stirred suspension of theproduct of Example 20d (1.2 g, 3.6 mmol) in EtOAc (40 mL) at roomtemperature and the mixture was stirred for 45 minutes at roomtemperature. Cold saturated NaHCO₃ (40 mL) was added and shaken well ina separatory funnel. The organic layer was separated and dried overNa₂SO₄. The solvent was evaporated under reduced pressure to afford aviscous oil which was dissolved in CH₂Cl₂ (5 mL) and hexane (25 mL). Theresulting clear solution was left in a freezer at −10° C. for 4 hours togive title compound (1.05 g, 77%) as a yellow solid. mp 104° C. ¹H-NMR(300 MHz, CDCl₃) δ 8.05 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 6.39(s, 1H), 5.50 (s, 2H), 3.95-4.10 (mult, 1H), 3.13 (s, 3H), 1.60-2.10(mult, 7H), 1.15-1.30 (mult, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 143.1,142.1, 140.7, 136.0, 129.8, 127.9, 107.3, 68.6, 58.6, 44.4, 33.3, 25.5,25.0; mass spectrum (API-TIS) m/z 380 (MH⁺). Anal. calcd forC₁₇H₂₁N₃O₅S: C, 53.81; H, 5.58; N, 11.07; S, 8.45 Found C, 53.55; H,5.55; N, 10.83; S. 8.36.

Example 21 Assay for Ovine COX-1 and COX-2 activity

The ovine COX-1 and COX-2 activities and the measurement of theprostaglandin products synthesized were performed using the COXInhibitor Screening Assay (Cayman Chemical, Ann Arbor, Mich., which alsocontained the Prostaglandin Screening EIA Kit, used for prostaglandinquantification). The test compounds were dissolved at 50 times thehighest final reaction concentration in DMSO or any other suitablesolvent as stock solutions. These stock solutions were then diluted inthe same solvent. Eight glass test tubes (13×100 mm) were placed in a37° C. water bath. To each test tube was added 950 μL of reaction buffer(0.1 M Tris-HCl, pH 8.0, containing 5 mM EDTA, and 2 mM phenol), 10 μLof 100 M heme solution, and 10 μL (5 units) of either ovine COX-1 orCOX-2 and the resulting mixture was incubated with the enzyme for 2minutes. Twenty μL of the solvent was added to one tube (100% initialactivity or solvent control) and 20 μL of each dilution of the testcompound was added to one tube each. Each tube was vortexed immediatelyafter the addition. The enzyme was incubated with the inhibitor for 3.5minutes at 37° C. The enzymatic reaction was then initiated by theaddition of 10 μL of freshly prepared 10 mM arachidonic acid(neutralized with KOH), vortexed and then incubated for 2 minutes at 37°C. The reaction was terminated by the addition of 50 μL of 1 M HCl,vortexed and placed at room temperature. One hundred microliters of asaturated stannous chloride solution (50 mg/mL of 0.1 M HCl) was addedand the reaction mixture was allowed to stand at room temperature for atleast 5 minutes.

The prostaglandins (PG) produced in the reactions were assayed, after a2,000-fold dilution, using the Prostaglandin Screening EIA Kit (CaymanChemical, Ann Arbor, Mich.). The assay contains an antibody with broadspecificity for all the prostaglandin families (PGF, PGE, PGD, andthromboxane B-type) synthesized in the COX-1/COX 2 reactions. Thesynthesized prostaglandin competes with a PG-tagged acetylcholineesterase tracer for binding to the PG antibody. Binding of synthesizedPG lowers the colorimetric development of the Elhman's Reagent (computedas % B/B₀). The actual amount of synthesized PG was interpolated from astandard curve using known amounts of supplied prostaglandin E2 (PGE₂)(PGE₂ concentration vs. % B/B₀). The data generated were the mean istandard deviation of triplicate wells in the EIA for a single reactionat a given inhibitor concentration. A plot of % of control (i.e., thesolvent control without inhibitor) vs. test compound inhibitorconcentration for both isoenzymes was used to determine the IC₅₀'s forCOX-1 and COX-2 for that test compound. The IC₅₀ for the compounds aregiven in Table 1.

TABLE 1 IC₅₀ VALUES FOR COX-1 and COX-2 COX-1 COX-2 Test Compound IC₅₀(μM) IC₅₀ (μM) Indomethacin 0.18 0.35 Celecoxib  34 0.34 Example 1a 1003.3  Example 1b 190 10 Example 2a No inhibition up to 300 24 Example 2bNo inhibition up to 300 1.2  Example 3e  62  0.006 Example 3g Noinhibition up to 300 70 Example 5a No inhibition up to 300 12 Example 5bNo inhibition up to 300 33

The NSAID, indomethacin, did not show selectivity for either COX-1 orCOX-2. Celecoxib, a selective COX-2 inhibitor, used as a control, wasselective for COX-2. The results show that the nitrosated compounds(i.e., Examples 1b, 2b and 5b) have similar COX-2 selectivity as theirparent non-nitrosated compound (i.e., Example 1a, 2a and 5arespectively). Hence, nitrosation did not effect the COX-2 inhibitionproperties. The results show that the nitrosylated compound (i.e.,Example 3g) was not as potent as the parent non-nitrosylated compound(i.e., Example 3e). The nitrosylation of the sulfonamide group on theparent COX-2 inhibitor probably effected the COX-2 inhibition propertiesof the nitrosylated compound.

Example 22 Assay for Human COX-1 and COX-2 Activity

The human COX-1 and COX-2 activities and the measurement of theprostaglandin products synthesized were performed using the COXInhibitor Screening Assay (Cayman Chemical, Ann Arbor, Mich., which alsocontained the Prostaglandin Screening EIA Kit, used for prostaglandinquantification). The test compounds were dissolved at 50 times thehighest final reaction concentration in DMSO or any other suitablesolvent as stock solutions. These stock solutions were then diluted inthe same solvent. Eight glass test tubes (13×100 mm) were placed in a25° C. water bath. To each test tube was added 950 μL of reaction buffer(0.1 M Tris-HCl, pH 8.0, containing 5 mM EDTA, and 2 mM phenol), 10 μLof 100 M heme solution, and 10 μL (5 units) of either human COX-1 orCOX-2 and the resulting mixture incubated with the enzyme for 2 minutes.Twenty μL of the solvent was added to one tube (100% initial activity orsolvent control) and 20 μL of each dilution of the test compound wasadded to one tube each. Each tube was vortexed immediately after theaddition. The enzyme was incubated with the inhibitor for 20 minutes at25° C. The enzymatic reaction was then initiated by the addition of 10μL of freshly prepared 10 mM arachidonic acid (neutralized with KOH),vortexed and then incubated for 2 minutes (or, in some cases asindicated, 30 seconds) at 37° C. The reaction was terminated by theaddition of 50 μL of 1 M HCl, vortexed and placed at room temperature.One hundred microliters of a saturated stannous chloride solution (50mg/mL of 0.1 M HCl) was added and the reaction mixture was allowed tostand at room temperature for at least 5 min.

The prostaglandins (PG) produced in the reactions were assayed, after a2,000-fold dilution, using the Prostaglandin Screening EIA Kit (CaymanChemical, Ann Arbor, Mich.). The assay contains an antibody with broadspecificity for all the prostaglandin families (PGF, PGE, PGD, andthromboxane B-type) synthesized in the COX-1/COX 2 reactions. Thesynthesized prostaglandin competes with a PG-tagged acetylcholineesterase tracer for binding to the PG antibody. Binding of synthesizedPG lowers the colorimetric development of the Eliman's Reagent (computedas % B/B₀). The actual amount of synthesized PG was interpolated from astandard curve using known amounts of supplied prostaglandin E2 (PGE₂)(PGE₂ concentration vs. % B/B₀). The data generated were the mean ±standard deviation of triplicate wells in the EIA for a single reactionat a given inhibitor concentration. A plot of % of control (i.e., thesolvent control without inhibitor) vs. test compound inhibitorconcentration for both isoenzymes was used to determine the IC₅₀'s forCOX-1 and COX-2 for that test compound, when IC₅₀'s were calculated. The% inhibition for selected concentrations of inhibitors tested are givenin Table 2.

TABLE 2 % INHIBITION OF HUMAN COX-1 AND COX-2 COX-1 Inhibition COX-2Inhibition Test Compound (% at 100 μM) (% at 10 μM) Example 2a   0^(a)65 Example 2b   0^(a) 100  Example 4a  89^(b)  69^(b) Example 4b  49^(b) 91^(b) Example 19d 95 100  Example 19e  0 100  Example 20d 16 34Example 20e  0 37 ^(a)= Ovine COX-1 ^(b)= 30 second incubation witharachidonic acid substrate

The results show that the nitrosated compounds (i.e., Examples 2b, 5b,19e and 20e) have similar or slightly improved COX-2 selectivitycompared to their parent non-nitrosated compound (i.e., Example 2a, 4a,19d and 20d, respectively). Hence, nitrosation did not effect the COX-2inhibition properties and might improve the COX-2 inhibition properties.

Example 23 Preparation of Rat Aortic Smooth Muscle Rings

Male Sprague-Dawley rats (Charles River Laboratories (Wilmington, Mass.)were euthanized by intraperiton injection of a high dose of sodiumpentobarbitone (80-100 mg/kg). The thoracic aorta was rapidly excisedand immediately placed in a Petri dish containing warm (37° C.)oxygenated (95% O₂ and 5% CO₂) Kreb's buffer (composition permillimolar: NaCl (119); KCl (4.69); CaCl₂H₂O (2.52); MgSO₄.7H₂O (0.57);NaHCO₃ (25); NaH₂PO₄.H₂O (1.01) and glucose (11.1). Under a stereoscopicdissecting microscope, the aorta was cleaned, freed from adhering fatand connective tissues. The tissue was cut into ring segments, eachapproximately 2-3 mm in length.

For experiments to measure relaxation of the tissue under variousconditions, a stainless steel tissue holder and an U-shaped stainlesssteel wire were inserted into the lumen of the aortic ring. The tissueholder anchored the ring at the bottom of the organ bath whereas the endof the U-shaped steel wire was tied with fine silk thread so that itconnected to the FT-202 transducer. The tissue holder and the steel wirealong with the aortic ring were then suspended in a 5-mL double-jacketedtemperature-controlled glass organ bath (Radnoti Glass Technology, Inc.,Monrovia, Calif.) filled with fresh Kreb's buffer. A mixture of 95% O₂and 5% CO₂ was bubbled through a porous sintered disc at the bottom ofthe bath. The rings were given an initial resting tension of 1.5 g andthe preparation was allowed to equilibrate at the initial tension forabout 90 minutes. During this equilibration period, the bath fluid waschanged every 15 minutes and replaced with fresh prewarmed (37° C.)Kreb's buffer. The isometric tension of the aortic muscle at rest andits response to different stimuli were recorded on a Power Macintosh6100 computer via a MacLab 8/S computer interface (CB Sciences, Inc,Milford, Mass.) after an initial amplification through a low-noiseETH-400 bioamplifier (CB Sciences, Inc, Milford, Mass.). Contractileresponsiveness of the tissue strips was established with 10 μMphenylephrine and the strips were incubated with the drug for 20 minutesto establish a steady level of contraction. To test the relaxationeffects, test compounds were added to the phenylephrine-precontractedstrips in the tissue bath at cumulative concentrations of 0.1 μM to 0.1mM. Concentration of test compounds was increased only after relaxationat the previous concentration had reached a plateau level.

Example 24 Relaxation of Aortic Smooth Muscle Ring by Example 1

The tissue was prepared according to Example 23. The percent contractionof phenylephrine-contracted aortic smooth muscle rings induced byisosorbide dinitrate (ISDN), Example 1a and Example 1b (nitrate) wasmeasured. FIG. 1 shows that the parent non-nitrosated compound, Example1a, did not relax the aortic ring. The nitrosated compound, Example 1b,induced the relaxation of the aortic ring. The observed relaxation wasmore potent than that obtained by the nitrate compound, isosorbidedinitrate.

Example 25 Relaxation of Aortic Smooth Muscle Ring by Example 2

The tissue was prepared according to Example 23. The percent contractionof phenylephrine-contracted aortic smooth muscle rings induced byisosorbide dinitrate (ISDN), Example 2a and Example 2b (nitrate) wasmeasured. FIG. 2 shows that the parent non-nitrosated compound, Example2a, did not relax the aortic ring. The nitrosated compound, Example 2b,induced the relaxation of the aortic ring. The observed relaxation wassimilar to that obtained by the nitrate compound, isosorbide dinitrate.

Example 26 Relaxation of Aortic Smooth Muscle Ring by Example 3

The tissue was prepared according to Example 23. The percent contractionof phenylephrine-contracted aortic smooth muscle rings induced byS-nitrosoglutathione (GSNO), Example 3e and Example 3h (nitrosothiol)was measured. FIG. 3 shows that the parent non-nitrosylated compound,Example 3e, did not relax the aortic ring. The nitrosylated compound,Example 3h, induced the relaxation of the aortic ring. The observedrelaxation was similar to that obtained by the nitrosothiol compound,S-nitrosoglutathione.

Example 27 Relaxation of Aortic Smooth Muscle Ring by Example 20

The tissue was prepared according to Example 23. The percent contractionof phenylephrine-contracted aortic smooth muscle rings induced byisosorbide dinitrate (ISDN), Example 20d and Example 20e (nitrate) wasmeasured. FIG. 4 shows that the parent non-nitrosylated compound,Example 20d, did not relax the aortic ring. The nitrosated compound,Example 20e, induced the relaxation of the aortic ring. The observedrelaxation was similar to that obtained by the nitrate compound,isosorbide dinitrate.

Example 28 Anti-inflammatory Paw Edema Test for Example 2

The carrageenan-induced rat paw edema test was used to measureantiinflammatory activity. The paw edema test was performed according tothe method of Winter et al, Proc. Soc. Exp. Biol. Med. 111: 544-547,1962. Male Sprague-Dawley rats (200-250 g) were fasted for 24 hours withwater ad libitum. The rats were dosed intragastrically with testcompounds in a volume of 5 mL/kg. One hour after dosing the paw volumewas measured. Then each rat received a subplantar injection of 50 μl of1% suspension of carrageenan. Three hours later, the paw volume wasmeasured and compared with the initial volume measured immediately aftercarrageenan injection. The increase in paw volume is presented as themean±SEM for 5 rats per group. Data were analyzed by performing an ANOVAtest followed by a Student-Keuls post hoc test.

FIG. 5 shows that the parent non-nitrosated compound Example 2a, thenitrosated compound Example 2b and Celecoxib all reduced the paw volumeand, hence, these compounds have antiinflammatory activity. Thus,nitrosation did not effect the COX-2 inhibition properties of thecompounds.

The disclosure of each patent, patent application and publication citedor described in the present specification is hereby incorporated byreference herein in its entirety.

Although the invention has been set forth in detail, one skilled in theart will appreciate that numerous changes and modifications can be madeto the invention, and that such changes and modifications can be madewithout departing from the spirit and scope of the present invention.

What is claimed is:
 1. A compound of Formula (II) or a pharmaceuticallyacceptable salt thereof:

wherein: A—B is: (a) N—C; (b) C—N; or (c) N—N; when sides d and f aredouble bonds, and sides e and g are single bonds, —X²—Y²—Z²— is: (a)═CR⁴—CR⁴′═CR⁵—; (b) ═N—CR⁴═CR⁴′—; (c) ═N—CR⁴═N—; (d) ═CR⁴—N═CR⁴′—; (e)═CR⁴—N═N—; (f) ═N—N═CR⁴—; (g) ═N—N═N—; (h) ═CR⁴—CR⁵═N—; or (i)═CR^(2′)—CR⁵═N—; R² and R^(2′) taken together are:

or R^(2′) and R⁵ taken together with the carbon atoms to which they areattached are: (a) cycloalkyl; or (b) heterocyclic ring; R⁹⁷ is: (a)hydrogen; (b) alkylthio; (c) alkylsulfinyl; (d) alkylsulfonyl; (e)cyano; (f) carboxyl; (g) amino; (h) lower alkyl; (i) haloalkyl; (j)hydroxy; (k) alkoxy; (l) haloalkoxy; (m) alkylarylalkylamino; (n)aminoalkyl; (o) aminoaryl; (p) sulfonamido; (q) alkylsulfonamido; (r)arylsulfonamido; (s) heterocyclic ring; (t) hydroxyalkyl; or (u) nitro;a is an integer from 1 to 3; when sides e and g are double bonds, andsides d and f are single bonds, —X²—Y²—Z²— is: (a) —CR⁴═N—N═; (b)—N═N—CR⁴═; (c) —CR⁴═N—CR⁴′═; (d) —N═CR⁴—N═; (e) —CR⁴═CR⁴′—N═; (f)—N═CR⁴—CR⁵═; (g) —CR⁴═CR⁵—CR^(5′)═; or (h) —N═N—N═; when side g is adouble bond, and sides d, e and f are single bonds, —X²—Y²—Z²— is: (a)—C(O)—O—CR⁴═; (b) —C(O)—NR³—CR⁴═; (c) —C(O)—S—CR⁴═; or (d)—C(H)R⁴—C(OH)R⁵—N═; when sides d is a double bond, and sides e, f and gare single bonds, —X²—Y²—Z²— is: (a) ═CR⁴—O—C(O)—; (b) ═CR⁴—NR³—C(O)—;(c) ═CR⁴—S—C(O)—; or (d) ═N—C(OH)R⁴—C(H)R⁵—; when sides f is a doublebond, and sides d, e and g are single bonds, —X²—Y²—Z²— is: (a)—CH(R⁴)—CR⁵═N—; or (b) —C(O)—CR⁴—CR⁵—; when sides e is a double bond,and sides d, f and g are single bonds, —X²—Y²—Z²— is: (a)—N═CR⁴—CH(R⁵)—; or (b) —CR⁴═CR⁵—C(O)—; when sides d, e, f and g aresingle bonds, —X²—Y²—Z²— is: (a) —C(O)—CR⁴(R^(4′))—C(O)—; R¹ is: (a)—S(O)₂—CH₃; (b) —S(O)₂—NR⁸(D¹); (c) —S(O)₂—N(D¹)—C(O)—CF₃; (d)—S(O)—(NH)—NH(D¹); (e) —S(O)—(NH)—N(D¹)—C(O)—CF₃; (f) —P(O)(CH₃)NH(D¹);(g) —P(O)(CH₃)₂; (h) —C(S)—NH(D¹); (i) —S(O)(NH)CH₃; (j) —P(O)(CH₃)OD¹;or (k) —P(O)(CH₃)NH(D¹); R^(1′) is: (a) hydrogen; (b) halogen; (c)methyl; or (d) CH₂OH; R² is: (a) lower alkyl; (b) cycloalkyl; (c) mono-,di- or tn-substituted phenyl or naphthyl, wherein the substituents areeach independently: (1) hydrogen; (2) halo; (3) alkoxy; (4) alkylthio;(5) CN; (6) haloalkyl; (7) lower alkyl; (8) N₃; (9) —CO₂D¹; (10)—CO₂-lower alkyl; (11) —(C(R⁵)(R⁶))_(z)—OD¹; (12)—(C(R⁵)(R⁶))_(z)—O-lower alkyl; (13) lower alkyl-CO₂—R⁵; (14) —OD¹; (15)haloalkoxy; (16) amino; (17) nitro; (18) alkylsulfinyl; or (19)heteroaryl; (d) mono-, di- or tri-substituted heteroaryl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or4 additional N atoms; wherein the substituents are each independently:(1) hydrogen; (2) halo; (3) lower alkyl; (4) alkoxy; (5) alkylthio; (6)CN; (7) haloalkyl; (8) N₃; (9) —C(R⁵)(R⁶)—OD¹; (10) —C(R⁵)(R⁶)—O-loweralkyl; or (11) alkylsulfinyl; (e) benzoheteroaryl which includes thebenzo fused analogs of (d); (f) —NR¹⁰R¹¹; (g) —SR¹¹; (h) —OR¹¹; (i)—R¹¹; (j) alkenyl; (k) alkynyl; (l) unsubstituted, mono-, di-, tri- ortetra-substituted cycloalkenyl, wherein the substituents are eachindependently: (1) halo; (2) alkoxy; (3) alkylthio; (4) CN; (5)haloalkyl; (6) lower alkyl; (7) N₃; (8) —CO₂D¹; (9) —CO₂-lower alkyl;(10) —C(R¹²)(R¹³)—OD¹; (11) —C(R¹²)(R¹³)—O-lower alkyl; (12) loweralkyl-CO₂—R¹²; (13) benzyloxy; (14) —O-(lower alkyl)-CO₂R¹²; (15)—O-(lower alkyl)-NR¹²R¹³; or (16) alkylsulfinyl; (m) mono-, di-, tri- ortetra-substituted heterocycloalkyl group of 5, 6 or 7 members, or abenzoheterocycle, wherein said heterocycloalkyl or benzoheterocycle has1 or 2 heteroatoms selected from O, S, or N and, optionally, a carbonylgroup or a sulfonyl group, and wherein said substituents are eachindependently: (1) halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5)CN; (6) haloalkyl; (7) N₃; (8) —C(R¹²)(R¹³)—OD¹; (9)—C(R¹²)(R¹³)—O-lower alkyl; or (10) alkylsulfinyl; (n) styryl, mono ordi-substituted styryl, wherein the substituent are each independently:(1) halo; (2) alkoxy; (3) alkylthio; (4) CN; (5) haloalkyl; (6) loweralkyl; (7) N₃; (8) —CO₂D¹; (9) —CO₂-lower alkyl; (10)—C(R¹²)(R¹³)—OD_(u); (11) —C(R¹²)(R¹³)—O-lower alkyl; (12) loweralkyl-CO₂—R¹²; (13) benzyloxy; (14) —O-(lower alkyl)-CO₂R¹²; or (15)—O-(lower alkyl)-NR¹²R¹³; (o) phenylacetylene, mono- or di-substitutedphenylacetylene, wherein the substituents are each independently: (1)halo; (2) alkoxy; (3) alkylthio; (4) CN; (5) haloalkyl; (6) lower alkyl;(7) N₃; (8) —CO₂D¹; (9) —CO₂-lower alkyl; (10) —C(R¹²)(R¹³)—OD¹; (11)—C(R¹²)(R¹³)—O-lower alkyl; (12) lower alkyl-CO₂—R¹²; (13) benzyloxy;(14) —O-(lower alkyl)-CO₂R¹²; or (15) —O-(lower alkyl)-NR¹²R¹³; (p)fluoroalkenyl; (q) mono- or di-substituted bicyclic heteroaryl of 8, 9or 10 members, consisting of 2, 3, 4 or 5 heteroatoms, wherein at leastone heteroatom resides on each ring of said bicyclic heteroaryl, saidheteroatoms are each independently O, S and N and said substituents areeach independently: (1) hydrogen; (2) halo; (3) lower alkyl; (4) alkoxy;(5) alkylthio; (6) CN; (7) haloalkyl; (8) N₃; (9) —C(R⁵)(R⁶)—OD¹; or(10) —C(R⁵)(R⁶)—O-lower alkyl; (r) K; (s) aryl; (t) arylalkyl; (u)cycloalkylalkyl; (v) —C(O)R¹¹; (u) hydrogen; (v) arylalkenyl; (w)arylalkoxy; (x) alkoxy; (y) aryloxy; (z) cycloalkoxy; (aa) arylthio;(bb) alkylthio; (cc) arylalkylthio; or (dd) cycloalkylthio; R³ is: (a)hydrogen; (b) haloalkyl; (c) CN; (d) lower alkyl; (e)—(C(R_(e))(R_(f)))_(p)—U—V; (f) K; (g) unsubstituted or substituted: (1)lower alkyl-Q; (2) lower alkyl-O-lower alkyl-Q; (3) lower alkyl-S-loweralkyl-Q; (4) lower alkyl-O—Q; (5) lower alkyl-S—Q; (6) lower alkyl-O—V;(7) lower alkyl-S—V; (8) lower alkyl-O—K; or (9) lower alkyl-S—K;wherein the substituent(s) reside on the lower alkyl group; (h) Q; (i)alkylcarbonyl; (j) arylcarbonyl; (k) alkylarylcarbonyl; (l)arylalkylcarbonyl; (m) carboxylic ester; (n) carboxamido; (o)cycloalkyl; (p) mono-, di- or tn-substituted phenyl or naphthyl, whereinthe substituents are each independently: (1) hydrogen; (2) halo; (3)alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl; (7) lower alkyl; (8) N₃;(9) —CO₂D¹; (10) —CO₂-lower alkyl; (11) —(C(R⁵)(R⁶))_(z)—OD¹; (12)—(C(R⁵)(R⁶))_(z)—O-lower alkyl; (13) lower alkyl-CO₂—R⁵; (14) —OD¹; (15)haloalkoxy; (16) amino; (17) nitro; or (18) alkylsulfinyl; (q) alkenyl;(r) alkynyl; (s) arylalkyl; (t) lower alkyl-OD¹; (u) alkoxyalkyl; (v)aminoalkyl; (w) lower alkyl-CO₂R¹⁰; (x) lower alkyl-C(O)NR¹⁰(R^(10′));(y) heterocyclicalkyl; or (z) heterocyclic ring-C(O)—; R⁴, R⁴′, R⁵ andR⁵′ are each independently: (a) hydrogen; (b) amino; (c) CN; (d) loweralkyl; (e) haloalkyl; (f) alkoxy; (g) alkylthio; (h) Q; (i) —O—Q; (j)—S—Q; (k) K; (l) cycloalkoxy; (m) cycloalkylthio; (n) unsubstituted,mono-, or di-substituted phenyl or unsubstituted, mono-, or di-substituted benzyl, wherein the substituents are each independently: (1)halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl;(7) N₃; (8) Q; (9) nitro; or (10) amino; (o) unsubstituted, mono-, ordi-substituted heteroaryl or unsubstituted, mono-, or di-substitutedheteroarylmethyl, wherein the heteroaryl is a monocyclic aromatic ringof 5 atoms, said ring having one heteroatom which is S, O, or N, and,optionally, 1, 2, or 3 additional N atoms; or the heteroaryl is amonocyclic ring of 6 atoms, said ring having one heteroatom which is N,and, optionally, 1, 2, 3, or 4 additional N atoms; tsaid substituentsare each independently: (1) halo; (2) lower alkyl; (3) alkoxy; (4)alkylthio; (5) CN; (6) haloalkyl; (7) N₃; (8) —C(R⁶)(R⁷)—OD¹; (9)—C(R⁶)(R⁷)—O-lower alkyl; or (10) alkylsulfinyl (p) —CON(R⁸)(R⁸); (q)—CH₂OR⁸; (r) —CH₂OCN; (s) unsubstituted or substituted: (1) loweralkyl-Q; (2) —O-lower alkyl-Q; (3) —S-lower alkyl-Q; (4) loweralkyl-O-lower alkyl-Q; (5) lower alkyl-S-lower alkyl-Q; (6) loweralkyl-O—Q; (7) lower alkyl-S—Q; (8) lower alkyl-O—K; (9) loweralkyl-S—K; (10) lower alkyl-O—V; or (11) lower alkyl-S—V; wherein thesubstituent(s) resides on the lower alkyl; (t) cycloalkyl; (u) aryl; (v)arylalkyl; (w) cycloalkylalkyl; (x) aryloxy; (y) arylalkoxy; (z)arylalkylthio; (aa) cycloalkylalkoxy; (bb) heterocycloalkyl; (cc)alkylsulfonyloxy; (dd) alkylsulfonyl; (ee) arylsulfonyl; (ff)arylsulfonyloxy; (gg) —C(O)R¹⁰; (hh) nitro; (ii) amino; (jj) aminoalkyl;(kk) —C(O)-alkyl-heterocyclic ring; (ll) halo; (mm) heterocyclic ring;(nn) —CO₂D¹; (oo) carboxyl; (pp) amidyl; or (qq) alkoxyalkyl;alternatively, R⁴ and R⁵ together with the carbons to which they areattached are: (a) cycloalkyl; (b) aryl; or (c) heterocyclic ring;alternatively, R⁴ and R⁴ or R⁵ and R^(5′) taken together with the carbonto which they are attached are: (a) cycloalkyl; or (b) heterocyclicring; alternatively, R⁴ and R⁵, R^(4′) and R^(5′), R^(4′) and R^(5′), orR^(4′) and R⁵ when substituents on adjacent carbon atoms taken togetherwith the carbons to which they are attached are: (a) cycloalkyl; (b)heterocyclic ring; or (c) aryl; R⁶ and R⁷ are each independently: (a)hydrogen; (b) unsubstituted, mono- or di-substituted phenyl;unsubstituted, mono- or di-substituted benzyl; unsubstituted, mono- ordi-substituted heteroaryl; mono- or di- substituted heteroarylmethyl,wherein said substituents are each independently: (1) halo; (2) loweralkyl; (3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl; (7) N₃; (8)—C(R¹⁴)(R¹⁵)—OD¹; or (9) —C(R¹⁴)(R¹⁵)—O-lower alkyl; (c) lower alkyl;(d) —CH₂OR⁸; (e) CN; (f) —CH₂CN; (g) haloalkyl; (h) —CON(R⁸)(R⁸); (i)halo; or (j) —OR⁸; R⁸ is: (a) hydrogen; (b) K; or (c) R⁹; alternatively,R⁵ and R⁵′, R⁶ and R⁷ or R⁷ and R⁸ together with the carbon to whichthey are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7atoms; and optionally up to two heteroatoms selected from oxygen,S(O)_(o) or NR_(i); R⁹ is: (a) lower alkyl; (b) lower alkyl-CO₂D¹; (c)lower alkyl-NHD¹; (d) phenyl or mono-, di- or tn-substituted phenyl,wherein the substituents are each independently: (1) halo; (2) loweralkyl; (3) alkoxy; (4) alkylthio; (5) lower alkyl-CO₂D¹; (6) loweralkyl-NHD¹; (7) CN; (8) CO₂D¹; or (9) haloalkyl; (e) benzyl, mono-, di-or tn-substituted benzyl, wherein the substituents are eachindependently: (1) halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5)lower alkyl-CO₂D¹; (6) lower alkyl-NHD¹; (7) CN; (8) —CO₂D¹; or (9)haloalkyl; (f) cycloalkyl; (g) K; or (h) benzoyl, mono-, di-, ortrisubstituted benzoyl, wherein the substituents are each independently:(1) halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5) loweralkyl-CO₂D¹; (6) lower alkyl-NHD¹; (7) CN; (8) —CO₂D¹; or (9) haloalkyl;R¹⁰ and R¹⁰′ are each independently: (a) hydrogen; or (b) R¹¹; R¹¹ is:(a) lower alkyl; (b) cycloalkyl; (c) unsubstituted, mono-, di- ortn-substituted phenyl or naphthyl, wherein the substituents are eachindependently: (1) halo; (2) alkoxy; (3) alkylthio; (4) CN; (5)haloalkyl; (6) lower alkyl; (7) N₃; (8) —CO₂D¹; (9) —CO₂-lower alkyl;(10) —C(R¹²)(R¹³)—OD¹; (11) —C(R¹²)(R¹³)—O-lower alkyl; (12) loweralkyl-CO₂D¹; (13) lower alkyl-CO₂R¹²; (14) benzyloxy; (15) —O-(loweralkyl)-CO₂D¹; (16) —O-(lower alkyl)-CO₂R¹²; or (17) —O-(loweralkyl)-NR¹²R¹³; (d) unsubstituted, mono-, di- or tn-substitutedheteroaryl, wherein the heteroaryl is a monocyclic aromatic ring of 5atoms, said ring having one heteroatom which is S, O, or N, and,optionally, 1, 2, or 3 additional N atoms; or said heteroaryl is amonocyclic ring of 6 atoms, said ring having one heteroatom which is N,and, optionally 1, 2, or 3 additional N atoms, and wherein saidsubstituents are each independently: (1) halo; (2) lower alkyl; (3)alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl; (7) N₃; (8)—C(R¹²)(R¹³)—OD¹; or (9) —C(R¹²)(R¹³)—O-lower alkyl; (e) unsubstituted,mono- or di-substituted benzoheterocycle, wherein the benzoheterocycleis a 5, 6, or 7-membered ring with 1 or 2 heteroatoms independentlyselected from O, S, or N, and, optionally, a carbonyl group or asulfonyl group, wherein said substituents are each independently: (1)halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl;(7) N₃; (8) —C(R¹²)(R¹³)—OD¹; or (9) —C(R¹²)(R¹³)—O-lower alkyl; (f)unsubstituted, mono- or di-substituted benzocarbocycle, wherein thecarbocycle is a 5, 6, or 7-membered ring has optionally a carbonylgroup, wherein said substituents are each independently: (1) halo; (2)lower alkyl; (3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl; (7) N₃;(8) —C(R¹²)(R¹³)—OD¹; or (9) —C(R¹²)(R¹³)—O-lower alkyl; (g) hydrogen;or (h) K R¹² and R¹³ are each independently: (a) hydrogen; (b) loweralkyl; or (c) aryl; or R¹² and R¹³ together with the atom to which theyare attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms;R¹⁴ and R¹⁵ are each independently: (a) hydrogen; or (b) lower alkyl; orR¹⁴ and R¹⁵ together with the atom to which they are attached form acarbonyl, a thial, or a saturated monocyclic ring of 3, 4, 5, 6 or 7atoms; D¹is: (a) hydrogen or (b) D; D is: (a) V; or (b) K; U is: (a)oxygen; (b) sulfur; or (c) —N(R_(a))R_(i)—; V is: (a) —No; (b) —NO₂; or(c) hydrogen K is—W_(aa)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(j)—W_(g)—(C(R_(e))(R_(f)))_(z)—U—V;wherein aa, b, c, d, g, i and j are each independently an integer from 0to 3; p, x, y and z are each independently an integer from 0 to 10; W ateach occurrence is independently: (a) —C(O)—; (b) —C(S)—; (c) —T—; (d)—(C(R_(e))(R_(f)))_(h)—; (e) alkyl; (f) aryl; (g) heterocyclic ring; (h)arylheterocyclic ring, or (i) —(CH₂CH₂O)_(q)—; E at each occurrence isindependently: (a) —T—; (b) alkyl; (c) aryl; (d)—(C(R_(e))(R_(f)))_(h)—; (e) heterocyclic ring; (f) arylheterocyclicring; or (g) —(CH₂CH₂O)_(q)—; h is an integer form 1 to 10; q is aninteger from 1 to 5; R_(e) and R_(f) are each independently: (a)hydrogen; (b) alkyl; (c) cycloalkoxy; (d) halogen; (e) hydroxy; (f)hydroxyalkyl; (g) alkoxyalkyl; (h) arylheterocyclic ring; (i)cycloalkylalkyl; (j) heterocyclicalkyl; (k) alkoxy; (l) haloalkoxy; (m)amino; (n) alkylamino; (o) dialkylamino; (p) arylamino; (q) diarylamino;(r) alkylarylamino; (s) alkoxyhaloalkyl; (t) haloalkoxy; (u) sulfonicacid; (v) alkylsulfonic acid; (w) arylsulfonic acid; (x) arylalkoxy; (y)alkylthio; (z) arylthio; (aa) cyano; (bb) aminoalkyl; (cc) aminoaryl;(dd) alkoxy; (ee) aryl; (ff) arylalkyl; (gg) carboxamido; (hh)alkylcarboxamido; (ii) arylcarboxamido; (jj) amidyl; (kk) carboxyl; (ll)carbamoyl; (mm) alkylcarboxylic acid; (nn) arylcarboxylic acid; (oo)alkylcarbonyl; (pp) arylcarbonyl; (qq) ester; (rr) carboxylic ester;(ss) alkylcarboxylic ester; (tt) arylcarboxylic ester; (uu) haloalkoxy;(vv) sulfonamido; (ww) alkylsulfonamido; (xx) arylsulfonamido; (yy)alkylsulfonyl, (zz) alkylsulfonyloxy, (aaa) arylsulfonyl, (bbb)arylsulphonyloxy (ccc) sulfonic ester; (ddd) carbamoyl; (eee) urea;(fff) nitro; or (ggg) —U—V; or R_(e) and R_(f) taken together are: (a)oxo; (b) thial; or R_(e) and R_(f) taken together with the carbon towhich they are attached are: (a) heterocyclic ring; (b) cycloalkylgroup; or (c) bridged cycloalkyl group; k is an integer from 1 to 2; Tat each occurrence is independently: (a) a covalent bond, (b) carbonyl,(c) an oxygen, (d) —S(O)_(o)—; or (e) —N(R_(a))R_(i)—; o is an integerfrom 0 to 2; Q is: (a) —C(O)—U—D¹; (b) —CO₂-lower alkyl; (c)tetrazolyl-5-yl; (d) —C(R⁷)(R⁸)(S—D¹); (e) —C(R⁷)(R⁸)(O—D¹); or (f)—C(R⁷)(R⁸)(O-lower alkyl); R_(a) is: (a) a lone pair of electron; (b)hydrogen; or (c) lower alkyl; R_(i) is: (a) hydrogen; (b) alkyl; (c)aryl; (d) alkylcarboxylic acid; (e) arylcarboxylic acid; (f)alkylcarboxylic ester; (g) arylcarboxylic ester; (h) alkylcarboxamido;(i) arylcarboxamido; (j) alkylsulfinyl; (k) alkylsulfonyl; (l)alkylsulfonyloxy, (m) arylsulfinyl; (n) arylsulfonyl; (o)arylsulphonyloxy; (p) sulfonamido; (q) carboxamido; (r) carboxylicester; (s) aminoalkyl; (t) aminoaryl; (u) —CH₂—C(U—V)(R_(e))(R_(f)); (v)a bond to an adjacent atom creating a double bond to that atom; or (w)—(N₂O₂—)⁻.M⁺, wherein M⁺ is an organic or inorganic cation; with theproviso that the compounds of Formula II must contain at least onenitrite, nitrate, thionitrite or thionitrate group.
 2. A compositioncomprising the compound of claim 1 and a pharmaceutically acceptablecarrier.
 3. A method for treating or reducing inflammation, pain orfever in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim2.
 4. A method for treating a gastrointestinal disorder, or improvingthe gastrointestinal properties of a COX-2 inhibitor in a patient inneed thereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim
 2. 5. The method of claim4, wherein the gastrointestinal disorder is an inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer,gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellisonsyndrome, gastroesophageal reflux disease, a bacterial infection,short-bowel (anastomosis) syndrome, or a hypersecretory state associatedwith systemic mastocytosis or basophilic leukemia and hyperhistaminemia.6. A method for facilitating wound healing in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 2. 7. The method of claim 6, whereinthe wound is an ulcer.
 8. A method for treating or reversing renaltoxicity in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim2.
 9. A method for treating a disorder resulting from elevated levels ofCOX-2 in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim2.
 10. The method of claim 9, wherein the disorder resulting fromelevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis,menstrual cramps, premature labor, tendinitis, bursitis, skin-relatedcondition, neoplasia, inflammatory processes in diseases, ophthalmicdisorder, pulmonary inflammation, central nervous system disorder,allergic rhinitis, respiratory distress syndrome, endotoxin shocksyndrome, atherosclerosis, inflammation and/or microbial infection,cardiovascular disorder, urinary and/or urological disorder, endothelialdysfunction, preservation of organs and tissues, inhibition ofactivation, adhesion and infiltration of neutrophils at the site ofinflammation, or inhibition of platelet aggregation.
 11. The method ofclaim 10, wherein the neoplasia is a brain cancer, a bone cancer, anepithelial cell-derived neoplasia (epithelial carcinoma), a basal cellcarcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, amouth cancer, an esophageal cancer, a small bowel cancer, a stomachcancer, a colon cancer, a liver cancer, a bladder cancer, a pancreascancer, an ovary cancer, a cervical cancer, a lung cancer, a breastcancer, a skin cancer, a squamus cell cancer, a basal cell cancer, aprostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, apolyp, an adenomatous polyp, a familial adenomatous polyposis or afibrosis resulting from radiation therapy.
 12. The method of claim 10,wherein the central nervous system disorder is cortical dementias,Alzheimer's disease, vascular dementia, multi-infarct dementia,pre-senile dementia, alcoholic dementia, senile dementia, or centralnervous system damage resulting from stroke, ischemia or trauma.
 13. Amethod for inhibiting platelet aggregation in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 2. 14. The composition of claim 2,further comprising at least one therapeutic agent.
 15. The compositionof claim 14, wherein the therapeutic agent is a steroid, a nonsteroidalantiinflammatory compound, a 5-lipoxygenase inhibitor, a leukotriene B₄receptor antagonist, a leukotriene A₄ hydrolase inhibitor, a 5-HTagonist, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, a H₂receptor antagonist, an antineoplastic agent, an antiplatelet agent, adecongestant, a diuretic, a sedating or non-sedating anti-histamine, aninducible nitric oxide synthase inhibitor, an opioid, an analgesic, aHelicobacter pylon inhibitor, a proton pump inhibitor, an isoprostaneinhibitor, or a mixture thereof.
 16. A method for treating, or reducinginflammation, pain or fever in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim
 14. 17. A method for treating a gastrointestinaldisorder, or improving the gastrointestinal properties of a COX-2inhibitor in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim14.
 18. The method of claim 17, wherein the gastrointestinal disorder isan inflammatory bowel disease, Crohn's disease, gastritis, irritablebowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, ableeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterialinfection, short-bowel (anastomosis) syndrome, or a hypersecretory stateassociated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia.
 19. A method for facilitating wound healing in apatient in need thereof comprising administering to the patient atherapeutically effective amount of the composition of claim
 14. 20. Themethod of claim 19, wherein the wound is an ulcer.
 21. A method fortreating or reversing renal toxicity in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 14. 22. A method for treating adisorder resulting from elevated levels of COX-2 in a patient in needthereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim
 14. 23. The method of claim22, wherein the disorder resulting from elevated levels of COX-2 isangiogenesis, arthritis, asthma, bronchitis, menstrual cramps, prematurelabor, tendinitis, bursitis, skin-related condition, neoplasia,inflammatory processes in diseases, ophthalmic disorder, pulmonaryinflammation, central nervous system disorder, allergic rhinitis,respiratory distress syndrome, endotoxin shock syndrome,atherosclerosis, inflammation and/or microbial infection, cardiovasculardisorder, urinary and/or urological disorder, endothelial dysfunction,preservation of organs and tissues, inhibition of activation, adhesionand infiltration of neutrophils at the site of inflammation, orinhibition of platelet aggregation.
 24. The method of claim 23, whereinthe neoplasia is a brain cancer, a bone cancer, an epithelialcell-derived neoplasia (epithelial carcinoma), a basal cell carcinoma,an adenocarcinoma, a gastrointestinal cancer, a lip cancer, a mouthcancer, an esophageal cancer, a small bowel cancer, a stomach cancer, acolon cancer, a liver cancer, a bladder cancer, a pancreas cancer, anovary cancer, a cervical cancer, a lung cancer, a breast cancer, a skincancer, a squamus cell cancer, a basal cell cancer, a prostate cancer, arenal cell carcinoma, a cancerous tumor, a growth, a polyp, anadenomatous polyp, a familial adenomatous polyposis or a fibrosisresulting from radiation therapy.
 25. The method of claim 23, whereinthe central nervous system disorder is cortical dementias, Alzheimer'sdisease, vascular dementia, multi-infarct dementia, pre-senile dementia,alcoholic dementia, senile dementia, or central nervous system damageresulting from stroke, ischemia or trauma.
 26. A method for inhibitingplatelet aggregation in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim
 14. 27. A composition comprising at least onecompound of claim 1 or a pharmaceutically acceptable salt thereof, andat least one compound that donates, transfers or releases nitric oxide,or induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase.
 28. The composition of claim 27 further comprising apharmaceutically acceptable carrier.
 29. The composition of claim 27,wherein the compound that donates, transfers, or releases nitric oxide,or induces the production of endogenous nitric oxide orendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase is an S-nitrosothiol.
 30. The composition of claim 29, whereinthe S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine, S-nitroso-glutathione, orS-nitroso-cysteinyl-glycine.
 31. The composition of claim 29, whereinthe S-nitrosothiol is: (i) HS(C(R_(e))(R_(f)))_(mm)SNO; (ii)ONS(C(R_(e))(R_(f)))_(mm)R_(e); or (iii)H₂N—CH(CO₂H)—(CH₂)_(mm)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H; wherein mm isan integer from 2 to 20; R_(e) and R_(f) are each independently ahydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, anhydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an alkoxy, an aryl, an arylalkyl, a carboxamido, aalkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, acarbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, analkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, asulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl,an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a carbamoyl, aurea, a nitro, —T—Q—, or (C(R_(e))(R_(f)))_(k)—T—Q, or R_(e) and R_(f)taken together are an oxo, a methanthial, a heterocyclic ring, acycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO₂; and Tis independently a covalent bond, a carbonyl, an oxygen, —S(O)_(o)— or—N(R_(a))R_(i)—, wherein o is an integer from 0 to 2, R_(a) is a lonepair of electrons, a hydrogen or an alkyl group; R_(i) is a hydrogen, analkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, anarylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, analkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl,a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, anaminoaryl,—CH₂—C(T—Q)(R_(e))(R_(f)), or —(N₂O₂—)⁻.M⁺, wherein M⁺ is anorganic or inorganic cation; with the proviso that when R_(i) is—CH₂—C(T—Q)(R_(e))(R_(f)) or —(N₂O₂—).M⁺; then “—T—Q” can be a hydrogen,an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxygroup or an aryl group.
 32. The composition of claim 27, wherein thecompound that donates, transfers, or releases nitric oxide, or inducesthe production of endogenous nitric oxide or endothelium-derivedrelaxing factor, or is a substrate for nitric oxide synthase isL-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine,nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, citrulline, ornithine, glutamine, or an arginaseinhibitor.
 33. The composition of claim 27, wherein the compound thatdonates, transfers, or releases nitric oxide, or induces the productionof endogenous nitric oxide or endothelium-derived relaxing factor, or isa substrate for nitric oxide synthase is: (i) a compound that comprisesat least one ON—O—, ON—N— or ON—C— group; (ii) a compound that comprisesat least one O₂N—O—, O₂N—N—, O₂N—S— or —O₂N—C— group; (iii) aN-oxo-N-nitrosoamine having the formula: R¹R²N—N(O—M⁺)—NO, wherein R¹and R² are each independently a polypeptide, an amino acid, a sugar, anoligonucleotide, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or aheterocyclic group, and M⁺ is an organic or inorganic cation.
 34. Thecomposition of claim 23, wherein the compound comprising at least oneON—O—, ON—N— or ON—C— group is an ON—O-polypeptide, an ON—N-polypeptide,an ON—C-polypeptide, an ON—O-amino acid, an ON—N-amino acid, anON—C-amino acid, an ON—O-sugar, an ON—N-sugar, an ON—C-sugar, anON—O-oligonucleotide, an ON—N-oligonucleotide, an ON—C-oligonucleotide,a straight or branched, saturated or unsaturated, substituted orunsubstituted, aliphatic or aromatic ON—O-hydrocarbon, a straight orbranched, saturated or unsaturated, substituted or unsubstituted,aliphatic or aromatic ON—N-hydrocarbon, a straight or branched,saturated or unsaturated, substituted or unsubstituted, aliphatic oraromatic ON—C-hydrocarbon, an ON—O-heterocyclic compound, anON—N-heterocyclic compound or a ON—C-heterocyclic compound.
 35. Thecomposition of claim 23, wherein compound comprising at least oneO₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— group is an O₂N—O-polypeptide, anO₂N—N-polypeptide, an O₂N—S-polypeptide, an O₂N—C-polypeptide, anO₂N—O-amino acid, O₂N—N-amino acid, O₂N—S-amino acid, an O₂N—C-aminoacid, an O₂N—O-sugar, an O₂N—N-sugar, O₂N—S-sugar, an O₂N—C-sugar, anO₂N-O-oligonucleotide, an O₂N—N-oligonucleotide, anO₂N—S-oligonucleotide, an O₂N—C-oligonucleotide, a straight or branched,saturated or unsaturated, aliphatic or aromatic, substituted orunsubstituted O₂N-O-hydrocarbon, a straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedO₂N—N-hydrocarbon, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted O₂N—S-hydrocarbon, astraight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted O₂N—C-hydrocarbon, an O₂N—O-heterocycliccompound, an O₂N—N-heterocyclic compound, an O₂N—S-heterocyclic compoundor an O₂N—C-heterocyclic compound.
 36. The composition of claim 27,further comprising at least one therapeutic agent.
 37. The compositionof claim 36, wherein the therapeutic agent is a steroid, a nonsteroidalantiinflammatory compound, a 5-lipoxygenase inhibitor, a leukotriene B₄receptor antagonist, a leukotriene A₄ hydrolase inhibitor, a 5-HTagonist, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, a H₂receptor antagonist, an antineoplastic agent, an antiplatelet agent, adecongestant, a diuretic, a sedating or non-sedating anti-histamine, aninducible nitric oxide synthase inhibitor, an opioid, an analgesic, aHelicobacter pylori inhibitor, a proton pump inhibitor, an isoprostaneinhibitor, or a mixture thereof.
 38. A method for treating, or reducinginflammation, pain or fever in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 28 or
 36. 39. A method for treating agastrointestinal disorder, or improving the gastrointestinal propertiesof a COX-2 inhibitor in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 28 or
 36. 40. The method of claim 39, wherein thegastrointestinal disorder is an inflammatory bowel disease, Crohn'sdisease, gastritis, irritable bowel syndrome, ulcerative colitis, apeptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity,dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophagealreflux disease, a bacterial infection, short-bowel (anastomosis)syndrome, or a hypersecretory state associated with systemicmastocytosis or basophilic leukemia and hyperhistaminemia.
 41. A methodfor facilitating wound healing in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 28 or
 38. 42. The method of claim 41, wherein thewound is an ulcer.
 43. A method for treating or reversing renal toxicityin a patient in need thereof comprising administering to the patient atherapeutically effective amount of the composition of claim 28 or 38.44. A method for treating a disorder resulting from elevated levels ofCOX-2 in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim28 or
 38. 45. The method of claim 44, wherein the disorder resultingfrom elevated levels of COX-2 is angiogenesis, arthritis, asthma,bronchitis, menstrual cramps, premature labor, tendinitis, bursitis,skin-related condition, neoplasia, inflammatory processes in diseases,ophthalmic disorder, pulmonary inflammation, central nervous systemdisorder, allergic rhinitis, respiratory distress syndrome, endotoxinshock syndrome, atherosclerosis, inflammation and/or microbialinfection, cardiovascular disorder, urinary and/or urological disorder,endothelial dysfunction, preservation of organs and tissues, inhibitionof activation, adhesion and infiltration of neutrophils at the site ofinflammation, or inhibition of platelet aggregation.
 46. The method ofclaim 45, wherein the neoplasia is a brain cancer, a bone cancer, anepithelial cell-derived neoplasia (epithelial carcinoma), a basal cellcarcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, amouth cancer, an esophageal cancer, a small bowel cancer, a stomachcancer, a colon cancer, a liver cancer, a bladder cancer, a pancreascancer, an ovary cancer, a cervical cancer, a lung cancer, a breastcancer, a skin cancer, a squamus cell cancer, a basal cell cancer, aprostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, apolyp, an adenomatous polyp, a familial adenomatous polyposis or afibrosis resulting from radiation therapy.
 47. The method of claim 45,wherein the central nervous system disorder is cortical dementias,Alzheimer's disease, vascular dementia, multi-infarct dementia,pre-senile dementia, alcoholic dementia, senile dementia, or centralnervous system damage resulting from stroke, ischemia or trauma.
 48. Amethod for inhibiting platelet aggregation in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claims 28 or
 36. 49. A kit comprising atleast one compound of claim 1 or a pharmaceutically acceptable saltthereof.
 50. The kit of claim 49, further comprising at least onecompound that donates, transfers or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, or is a substrate for nitric oxide synthase or at least onetherapeutic agent.
 51. The kit of claim 50, wherein the at least onecompound that donates, transfers or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, or is a substrate for nitric oxide synthase or the at least onetherapeutic agent are in the form of separate components in the kit. 52.A kit comprising the composition of claim 14, 27 or
 36. 53. A compoundselected from the group consisting of4-(5-(4-chlorophenyl)-3-((nitrooxy)methyl)-3-hydropyrazolyl)benzenesulfonamide, 1-(5-methyl-1-(2-methyl-2-(nitrosothio)propyl)pyrrol-2-yl)-4-(methylsulfonyl) benzene,2-methyl-2-(nitrosothio)propyl-5-(4-chlorophenyl)-1-(4-sulfamoylphenyl)pyrazole-3-carboxylate,4-{1-cyclohexyl-3-(nitrooxy)methyl)pyrazol-5-yl}-1-(methylsulfonyl)benzeneor a pharmaceutically acceptable salt thereof.
 54. A compositioncomprising at least one compound of claim 53 and a pharmaceuticallyacceptable carrier.
 55. A kit comprising at least one compound of claim53 or a pharmaceutically acceptable salt thereof.